Analogues of GLP-1

ABSTRACT

The present invention is directed to peptide analogues of glucagon-like peptide-1, the pharmaceutically-acceptable salts thereof, to methods of using such analogues to treat mammals and to pharmaceutical compositions useful therefor comprising said analogues.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase application filed under 35 U.S.C.371 of International Application No. PCT/EP99/09660, filed Dec. 7, 1999,and is a continuance-in-part of Ser. No. 09/206,601 filed Dec. 7, 1998now ABN which claims the benefit of U.S. application No. 60/111,255,filed Dec. 7, 1998, the contents of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

The present invention is directed to peptide analogues of glucagon-likepeptide-1, the pharmaceutically-acceptable salts thereof, to methods ofusing such analogues to treat mammals and to pharmaceutical compositionsuseful therefor comprising said analogues.

Glucagon-like peptide-1 (7-36) amide (GLP-1) (SEQ ID NO:1) issynthesized in the car intestinal L-cells by tissue-specificpost-translational processing of the glucagon precursor z Cpreproglucagon (Varndell, J. M., et al., J. Histochem Cytochem,1985:33:1080-6) and is released into the circulation in response to ameal. The plasma concentration of GLP-1 rises from a fasting level ofapproximately 15 pmol/L to a peak postprandial level of 40 pmol/L. Ithas been a demonstrated that, for a given rise in plasma glucoseconcentration, the increase in plasma insulin is approximately threefoldgreater when glucose is administered orally compared with intravenously(Kreymann, B., et al., Lancet 1987:2, 1300-4). This alimentaryenhancement of insulin release, known as the incretin effect, isprimarily humoral and GLP-1 is now thought to be the most potentphysiological incretin in humans. In addition to the insulinotropiceffect. GLP-1 suppresses glucagon secretion, delays gastric emptying(Wettergren A., et al., Dig Dis Sci 1993:38:665-73) and may enhanceperipheral glucose disposal (D'Alessio, D. A. et al., J. Clin Invest1994:93:2293-6).

In 1994, the therapeutic potential of GLP-1 was suggested following theobservation that a single subcutaneous (s/c) dose of GLP-1 couldcompletely normalize postprandial glucose levels in patients withnon-insulin-dependent diabetes mellitus (NIDDM) (Gutniak, M. K. et al.Diabetes Care 1994:17:1039-44). This effect was thought to be mediatedboth by increased insulin release and by a reduction in glucagonsecretion. Furthermore, an intravenous infusion of GLP-1 has been shownto delay postprandial gastric emptying in patients with NIDDM (Williams,B., et al., J. Clin Endo Metab 1996:81:327-32). Unlike sulphonylureas,the insulinotropic action of GLP-1 is dependent on plasma glucoseconcentration (Holz, G. G. 4^(th), et al., Nature 1993:361:362-5). Thus,the loss of GLP-1-mediated insulin release at low plasma glucoseconcentration protects against severe hypoglycemia. This combination ofactions gives GLP-1 unique potential therapeutic advantages over otheragents currently used to treat NIDDM.

Numerous studies have shown that when given to healthy subjects, GLP-1potently influences glycemic levels as well as insulin and glucagonconcentrations (Orskov, C, Diabetologia 35:701-711, 1992; Hoist, J. J.,et a)., Potential of GLP-1 in diabetes management in Glucagon III,Handbook of Experimental Pharmacology, Lefevbre PJ, Ed. Berlin, SpringerVerlag, 1996, p. 311-326), effects which are glucose dependent(Kreymann, B., et al., Lancet ii: 1300-1304, 1987; Weir, G. C., et al.,Diabetes 38:338-342, 1989). Moreover, it is also effective in patientswith diabetes (Gutniak, M., N. Engl J Med 226:1316-1322, 1992; Nathan,D. M., et al., Diabetes Care 15:270-276, 1992), normalizing bloodglucose levels in type 2 diabetic subjects (Nauck, M. A., et al.,Diagbetologia 36:741-744, 1993), and improving glycemic control in typeI patients (Creutzfeldt, W. O., et al., Diabetes Care 19:580-586, 1996),raising the possibility of its use as a therapeutic agent.

GLP-1 is, however, metabolically unstable, having a plasma half-life(t_(1/2)) of only 1-2 min in vivo. Exogenously administered GLP-1 isalso rapidly degraded (Deacon, C. F., et al., Diabetes 44:1126-1131,1995). This metabolic instability limits the therapeutic potential ofnative GLP-1. Hence, there is a need for GLP-1 analogues that are moreactive or are more metabolically stable than native GLP-1.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to a compound offormula (I),(R²R³)-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-  (1)A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-A³⁹-R¹ (SEQ ID NO:412),wherein

-   A⁷ is L-His, Ura, Paa, Pta, Amp, Tma-His, des-amino-His, or deleted;-   A⁸ is Ala, D-Ala, Aib, Ace, N-Me-Ala, N-Me-D-Ala or N-Me-Gly;-   A⁹ is Glu, N-Me-Glu, N-Me-Asp or Asp;-   A¹⁰ is Gly, Ace, β-Ala or Aib;-   A¹¹ is Thr or Ser;-   A¹² is Phe, Acc, Aic, Aib, 3-Pal, 4-Pal, β-Nal, Cha, Trp or X¹-Phe;-   A¹³ is Thr or Ser;-   A¹⁴ is Ser or Aib;-   A¹⁵ is Asp or Glu;-   A¹⁶ is Val, Acc, Aib, Leu, Ile, Tle, Nle, Abu, Ala or Cha;-   A¹⁷ is Ser or Thr;-   A¹⁸ is Ser or Thr;-   A¹⁹ is Tyr, Cha, Phe, 3-Pal, 4-Pal, Acc, β-Nal or X¹-Phe;-   A²⁰ is Leu, Acc, Aib, Nle, Ile, Cha, Tle, Val, Phe or X¹-Phe;-   A²¹ is Glu or Asp;-   A²² is Gly, Acc, β-Ala, Glu or Aib;-   A²³ is Gin, Asp, Asn or Glu;-   A²⁴ is Ala, Aib, Val, Abu, Tie or Acc;-   A²⁵ is Ala, Aib, Val, Abu, Tle, Acc, Lys, Arg, hArg, Orn,    HN—CH((CH₂)_(n)—N(R¹⁰-R¹¹))—C(O) or NH—CH((CH₂)—X³)—C(O);-   A²⁶ is Lys, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R¹⁰-R¹¹))-C(O) or    NH—CH((CH₂)_(e)X³)—C(O);-   A²⁷ is Glu Asp, Leu, Aib or Lys;-   A²⁸ is Phe, Pal, β-Nal, X¹-Phe, Aic, Acc, Aib, Cha or Trp;-   A²⁹ is Ile, Acc, Aib, Leu, Nle, Cha, Tie, Val, Abu, Ala or Phe;-   A³⁰ is Ala, Aib or Acc;-   A³¹ is Trp, β-Nal, 3-Pal, 4-Pal, Phe, Acc, Aib or Cha;-   A³² is Leu, Acc, Aib, Nle, Ile, Cha, Tie, Phe, X¹-Phe or Ala;-   A³³ is Val, Acc, Aib, Leu, Ile, Tle, Nle, Cha, Ala, Phe, Abu, Lys or    X¹-Phe;-   A³⁴ is Lys, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R¹⁰-R¹¹))—C(O) or    NH—CH((CH₂)_(e)—X³)—C(O);-   A³⁵ is Gly, β-Ala, D-Ala, Gaba, Ava, NH—(CH₂)_(m)—C(O), Aib, Acc or    a D-amino acid,-   A³⁶ is L- or D-Arg, D- or L-Lys, D- or L-hArg, D- or L-Orn,    HN—CH((CH₂)_(n)—N(R¹⁰-R¹¹))—C(O), NH—CH((CH₂)_(e)-X³)—C(O) or    deleted;-   A³⁷ is Gly, β-Ala, Gaba, Ava, Aib, Acc, Ado, Arg, Asp, Aun, Aec,    NH—(CH₂)_(m)—C(O), HN—CH((CH₂)_(n)—N(R¹⁰-R¹¹))-C(O), a D-amino acid,    or deleted;-   A³⁸ is D- or L-Lys, D- or L-Arg, D- or L-hArg, D- or L-Orn,    HN—CH((CH₂)_(n)—N(R¹⁰-R¹¹))-C(O), NH—CH((CH₂)_(e)—X³)—C(O), Ava,    Ado, Aec or deleted;-   A³⁹ is D- or L-Lys, D- or L-Arg, HN—CH((CH₂)_(n)—N(R¹⁰-R¹¹))-C(O),    Ava, Ado, or Aec;-   X¹ for each occurrence is independently selected from the group    consisting of (C₁-C₆)alkyl, OH and halo;-   R¹ is OH, NH₂, (C₁-C₃₀) alkoxy, or NH—X²—CH₂—Z⁰, wherein X² is a    (C₁-C₁₂) hydrocarbon moiety, and Z⁰ is H, OH, CO₂H or CONH₂;    X³ is    or —C(O)—NHR¹², wherein X⁴ is, independently for each occurrence,    —C(O)—, —NH—C(O)— or —CH₂—and wherein f is, independently for each    occurrence, an integer from 1 to 29 inclusive, each of R² and R³ is    independently selected from the group consisting of H,    (C₁-C₃₀)alkyl, (C₂-C₃₀)alkenyl, phenyl(C₁-C₃₀)alkyl,    naphthyl(C₁-C₃₀)alkyl, hydroxy(C₁-C₃₀)alkyl, hydroxy(C₂-C₃₀)alkenyl,    hydroxyphenyl(C₁-C₃₀)alkyl, and hydroxynaphthyl(C₁-C₃₀)alkyl; or one    of R² and    (C₁-C₃₀)acyl, (C₁—C₃₀)alkylsulfonyl, C(O)X⁵,    wherein Y is H, OH or NH₂; r is 0 to 4; q is 0 to 4; and X⁵ is    (C₁-C₃₀)alkyl, (C₂-C₃₀)alkenyl, phenyl(C₁-C₃₀)alkyl,    naphthyl(C₁-C₃₀)alkyl, hydroxy(C₁-C₃₀)alkyl, hydroxy(C₂-C₃₀)alkenyl,    hydroxyphenyl(C₁-C₃₀)alkyl or hydroxynaphthyl(C₁-C₃₀)alkyl;-   e is, independently for each occurrence, an integer from 1 to 4    inclusive;-   m is, independently for each occurrence, an integer from 5 to 24    inclusive;-   n is, independently for each occurrence, an integer from 1 to 5,    inclusive;-   each of R¹⁰ and R¹¹ is, independently for each occurrence, H,    (C₁-C₃₀)alkyl, (C₁-C₃₀)acyl, (C₁-C₃₀)alkylsulfonyl, —C((NH)(NH₂)) or    and-   R¹² and R¹³ each is, independently for each occurrence,    (C₁-C₃₀)alkyl;    provided that:-   when A⁷ is Ura, Paa or Pta, then R² and R³ are deleted;-   when R¹⁰ is (C₁-C₃₀)acyl, (C₁-C₃₀)alkylsulfonyl, —C((NH)(NH₂)) or    then R¹¹ is H or (C₁-C₃₀)alkyl;-   (i) at least one amino acid of a compound of formula (I) is not the    same as the native sequence of hGLP-1(7-36, -37 or -38)NH₂ or    hGLP-1(7-36, -37 or -38)OH;-   (ii) a compound of formula (I) is not an analogue of hGLP-1 (7-36,    -37 or -38)NH₂ or hGLP-1(7-36, -37 or -38)OH wherein a single    position has been substituted by Ala;-   (iii) a compound of formula (I) is not (Arg^(26,34),    Lys³⁸)hGLP-1(7-38)-E, (Lys²⁶(N_(ε)-alkanoyl))hGLP-(7-36, -37 or    -38)-E, (Lys³⁴(N_(ε)-alkanoyl))hGLP-1(7-36, -37 or -38)-E,    (Lys^(26,34)-bis(N_(ε)-alkanoyl))hGLP-1(7-36, -37 or -38)-E, (Arg²⁶,    Lys³⁴(N_(ε)-alkanoyl))hGLP-1 (8-36, -37 or -38)-E, (Arg^(26,34),    Lys³⁶(N_(ε)-alkanoyl))hGLP-1(7-36, -37 or -38)-E or (Arg^(26,34),    Lys³⁸(N_(ε)-alkanoyl))hGLP-1(7-38)-E, wherein E is —OH or —NH₂;-   (iv) a compound of formula (I) is not Z¹-hGLP-1(7-36, -37 or    -38)—OH, Z¹-hGLP-1(7-36, -37 or -38)—NH₂, wherein Z¹ is selected    from the group consisting of:    -   (a) (Arg²⁶), (Arg³⁴), (Arg^(26,34)), (Lys³⁶), (Arg²⁶, Lys³⁶),        (Arg³⁴, Lys³⁶), (D-Lys³⁶), (Arg³⁶), (D-Arg³⁶), (Arg^(26,34),        Lys³⁶) or (Arg^(26,36), Lys³⁴);    -   (b) (Asp²¹);    -   (c) at least one of (Aib⁸), (D-Ala⁸) and (Asp⁹); and    -   (d) (Tyr⁷), (N-acyl-His⁷), (N-alkyl-His⁷), (N-acyl-D-His⁷) or        (N-alkyl-D-His⁷);    -   (v) a compound of formula (I) is not a combination of any two of        the substitutions listed in groups (a) to (d); and    -   (vi) a compound of formula (I) is not (N-Me-Ala⁸)hGLP-1(8-36 or        -37), (Glu¹⁵)hGLP-1(7-36 or -37), (Asp ²¹)hGLP-1(7-36 or -37) or        (Phe³¹)hGLP-1(7-36 or -37) or a pharmaceutically acceptable salt        thereof.

A preferred group of compounds of the immediately foregoing compound iswhere A¹¹ is Thr; A¹³ is Thr; A¹⁵ is Asp; A¹⁷ is Ser; A¹⁸ is Ser or Lys;A²¹ is Glu; A²³ is Gln or Glu; A²⁷ is Glu, Leu, Aib or Lys; and A³¹ isTrp, Phe or β-Nal; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group ofcompounds is where A⁹ is Glu, N-Me-Glu or N-Met-Asp; A¹² is Phe, Acc,β-Nal or Aic; A¹⁶ is Val, Acc or Aib; A¹⁹ is Tyr or β-Nal; A²⁰ is Leu,Acc or Cha; A²⁴ is Ala, Aib or Acc; A²⁵ is Ala, Aib, Acc, Lys, Arg,hArg, Orm, HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))-C(O) or HN—CH((CH₂)_(e)—X³)—C(O);A²⁸ is Phe or β-Nal; A²⁹ is Ile or Acc; A³⁰ is Ala or Aib; A³² is Leu,Acc or Cha; and A³³ is Val, Lys or Acc; or a pharmaceutically acceptablesalt thereof.

A preferred group of compounds of the immediately foregoing group ofcompounds is where A⁸ is Ala, D-Ala, Aib, A6c, A5c, N-Me-Ala, N-Me-D-Alaor N-Me-Gly; A¹⁰ is Gly; A¹² is Phe, β-Nal, A6c or A5c; A²⁶ is Val, A6cor A5° c.; A²⁰ is Leu, A6c, A5c or Cha; A²² is Gly, β-Ala, Glu or Aib;A²⁴ is Ala or Aib; A²⁹ is Ile, A6c or A5c; A³² is Leu, A6c, A5c or Cha;A³³ is Val, Lys, A6c or A5c; A³⁵ is Aib, β-Ala, Ado, A6c, A5c, D-Arg orGly; and A³⁷ is Gly, Aib, β-Ala, Ado, D-Ala, Ava, Asp, Aun, D-Asp,D-Arg, Aec, HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))-C(O) or deleted; or apharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group ofcompounds is where X⁴ for each occurrence is —C(O)—; and R¹ is OH orNH₂; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group ofcompounds or a pharmaceutically acceptable salt thereof is where R² is Hand R³ is (C₁-C₃₀)alkyl, (C₂-C₃₀)alkenyl, (C₁-C₃₀)acyl,(C₁-C₃₀)alkylsulfonyl,

A preferred compound of the formula (I) is where A⁸ is Ala, D-Ala, Aib,A6c, A5c, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A¹⁰ is Gly; A¹² is Phe,β-Nal, A6c or A5c; A¹⁶ is Val. A6c or A5c; A²⁰ is Leu, A6c, A5c or Cha;A²² is Gly, β-Ala, Glu or Aib; A²⁴ is Ala or Aib; A²⁹ is Ile, A6c orA5c; A³² is Leu, A6c, A5c or Cha; A³³ is Val, Lys, A6c or A5c; A³⁵isAib, β-Ala, Ado, A6c, A5c, D-Arg or Gly; and A³⁷ is Gly, Aib, β-Ala,Ado, D-Ala, Ava, Asp, Aun, D-Asp. D-Arg, Aec,HN—CH((CH₂)_(n)—N(R¹⁰R¹¹))-C(O) or deleted; X⁴ for each occurrence is—C(O)—; e for each occurrence is independently 1 or 2; R¹ is OH or NH₂;R¹⁰ is (C₁-C₃₀)acyl, (C₁-C₃₀)alkylsulfonyl or

and R¹¹ is H; or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing compounds is where R¹⁰ is(C₄-C₂₀)acyl, (C₄-C₂₀)alkylsulfonyl or

or apharmaceutically acceptable salt thereof.

A more preferred compound of formula (I) is where said compound is ofthe formula:

-   (Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:2),-   ((N_(α)-HEPES-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:3),-   ((N_(α)-HEPA-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:4),-   (Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:5),-   (Aib^(8,35), Arg^(26,34), Lys³⁶(Ne-tetradecanoyl))hGLP-1(7-36)NH₂    (SEQ ID NO:6),-   (Aib^(8,35), Arg^(26,34), Lys³⁴ (N-tetradecanoyl))hGLP-1(7-36)NH₂    (SEQ ID NO:7),-   (Aib^(8,35,37), Arg^(26,34), Lys³⁶(N-tetradecanoyl))hGLP-1 (7-38)NH₂    (SEQ ID NO:8),-   (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-decanoyl))hGLP-1 (7-36)NH₂    (SEQ ID NO:9),-   (Aib^(8,35), Arg^(26,34),    Lys³⁶(N_(ε)-dodecanesulfonyl))hGLP-1(7-36)NH₂ (SEQ ID NO:10).-   (Aib^(8,35), Arg^(26,34),    Lys³⁶(N_(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH₂    (SEQ ID NO:11),-   (Aib^(8,35), Arg^(26,34) ,    Asp³⁶(1-(4-tetradecyl-piperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:12),-   (Aib^(8,35), Arg^(26,34), Asp³⁶(1-tetradecylamino))hGLP-1(7-36)NH₂    (SEQ ID NO:13),-   (Aib^(8,35), Arg^(26,34), Lys ³⁶(N_(ε)-tetradecanoyl),    β-Ala³⁷)hGLP-1(7-37)—OH (SEQ ID NO: 14) or-   (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)—OH    (SEQ ID NO: 15), or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is acompound of the formula:

-   (Aib^(8,35))hGLP-1 (7-36)NH₂ (SEQ ID NO:2),-   (Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:5),-   (Aib^(8,35), Arg²⁶, Lys³⁴ (N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ    ID NO:7),-   (Aib^(8,35,37), Arg^(26,34),    Lys³⁸(N_(ε)-tetradecanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:8),-   (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ    ID NO:9), or-   (Aib^(8,35), Arg^(26,34) Lys³⁶(N_(ε)-tetradecanoyl), β-Ala³⁷)hGLP-1    (7-37)—OH (SEQ ID NO:14), or a pharmaceutically acceptable salt    thereof.

Another more preferred compound of formula (I) is where said compound isof the formula:

-   (Aib^(8,35), A6c³²)hGLP-1(7-36)NH₂ (SEQ ID NO:16);-   (Aib^(3,35), Glu²³)hGLP-1(7-36)NH₂ (SEQ ID NO:17);-   (Aib ^(8,24,35))hGLP-1 (7-36)NH₂ (SEQ ID NO:18);-   (Aib^(8,35), Glu²³, A6c³²)hGLP-1(7-36)NH₂ (SEQ ID NO: 19);-   (Aib⁸, Glu²³, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:20);-   (Aib^(8,35), Arg^(26,34))hGLP-1(7-36)NH₂ (SEQ ID NO:21);-   (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ    ID NO:22);-   (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-decanoyl))hGLP-1 (7-36)OH (SEQ    ID NO:23);-   (Aib^(8,35), Lys²⁵, Arg^(26,34) Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)OH    (SEQ ID NO:24);-   (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁶(N^(ε)-Aec    decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:25);-   (Aib^(8,35), Arg^(26,34), Ava³⁷, Ado³⁹)hGLP-1(7-38)NH₂ (SEQ ID    NO:26);-   (Aib^(8,35), Arg^(26,34), Asp³⁷, Ava³⁸, Ado³⁹)hGLP-1(7-39)NH₂ (SEQ    ID NO:27);-   (Aib^(8,35), Arg^(26,34), Aun³⁷)hGLP-1(7-37)NH₂ (SEQ ID NO:28);-   (Aib^(8,17,35))hGLP-1(7-36)NH₂ (SEQ ID NO:29);-   (Aib⁸ Arg^(26,34), β-Ala³⁵, D-Asp³⁷ Ava³⁸ Aun³⁹)hGLP-1(7-39)NH₂(SEQ    ID NO:30);-   (Gly⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:31);-   (Ser⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:32);-   (Aib⁸, Glu^(22,23), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:33);-   (Gly⁸, Aib³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:34);-   (Aib⁸, Lys¹⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO: 35);-   (Aib⁸, Leu²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:36);-   (Aib⁸, Lys³³, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:37);-   (Aib⁸, Lys¹⁸, Leu²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:38);-   (Aib⁸, D-Arg³⁶)hGLP-1(7-36)NH₂ (SEQ ID NO:39);-   (Aib⁸, β-Ala³⁵, D-Arg³⁷)hGLP-1(7-37)NH₂ (SEQ ID NO:40);-   (Aib^(8,27), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:41);-   (Aib^(8,27), β-Ala^(35,37), Arg³⁹)hGLP-1(7-38)NH₂ (SEQ ID NO:42);-   (Aib^(8,27), β-Ala^(35,37), Arg^(38,39))hGLP-1(7-39)NH₂(SEQ ID    NO:43);-   (Aib⁸ , Lys^(18,27), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:44);-   (Aib⁸, Lys²⁷, β-Ala³⁵)hGLP-1 (7-36)NH₂ (SEQ ID NO:45);-   (Aib⁸, β-Ala³⁵, Arg³⁸)hGLP-1(7-38)NH₂ (SEQ ID NO:46);-   (Aib⁸, Arg^(26,34) Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:47);-   (Aib⁸, D-Arg³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:48);-   (Aib⁸, β-Ala³⁵, Arg³⁷)hGLP-1(7-37)NH₂ (SEQ ID NO:49);-   (Aib⁸, Phe³¹, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:50);-   (Aib^(8,35), Phe³¹)hGLP-1(7-36)NH₂ (SEQ ID NO:51);-   (Aib^(8,35), Nal³¹)hGLP-1(7-36)NH₂ (SEQ ID NO:52);-   (Aib^(8,35), Nal^(28,31))hGLP-1 (7-36)NH₂ (SEQ ID NO:53);-   (Aib^(8,35), Arg^(26,34), Nal³¹)hGLP-1(7-36)NH₂ (SEQ ID NO:54);-   (Aib^(8,35) Arg^(26,34) Phe³¹)hGLP-1(7-36)NH₂(SEQ ID NO:55);-   (Aib^(8,35), Nal^(19,31))hGLP-1 (7-36)NH₂ (SEQ ID NO:56);-   (Aib^(8,35), Nal^(12,31))hGLP-1 (7-36)NH₂ (SEQ ID NO:57);-   (Aib^(8,35), Lys³⁶(N^(β)-decanoyl))hGLP-1 (7-36)NH₂ (SEQ ID NO:58);-   (Aib^(8,35), Arg³⁴, Lys²⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID    NO:59);-   (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-dodecanoyl))hGLP-1(7-36)NH₂    (SEQ ID NO:60);-   (Aib⁸, β-Ala³⁵, Ser³⁷(O-decanoyl))hGLP-1(7-37)—NH₂ (SEQ ID NO:61);-   (Aib^(8,27), β-Ala^(35,37), Arg³⁸,    Lys³⁹(N^(ε)-octanoyl))hGLP-1(7-39)NH₂ (SEQ ID NO:62);-   (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁷(N^(ε)-octanoyl))hGLP-1(7-37)NH₂    (SEQ ID NO:63);-   (Aib⁸, Arg^(26,34), β-Ala³⁵ Lys³⁷(N^(ε)-decanoyl))hGLP-1 (7-37)NH₂    (SEQ ID NO:64); or-   (Aib⁸, Arg^(26,34), β-Ala³⁵,    Lys³⁷(N^(ε)-tetradecanoyl))hGLP-1(7-37)NH₂ (SEQ ID NO:65);    or a pharmaceutically acceptable salt thereof.

Another more preferred compound of formula (I) is each of the compoundsthat are specifically enumerated hereinbelow in the Examples section ofthe present disclosure, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)as defined hereinabove or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable carrier of diluent.

In yet another aspect, the present invention provides a method ofeliciting an agonist effect from a GLP-1 receptor in a subject in needthereof which comprises administering to said subject an effectiveamount of a compound of formula (I) as defined hereinabove or apharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides a method of treatinga disease selected from the group consisting of Type I diabetes, Type IIdiabetes, obesity, glucagonomas, secretory disorders of the airway,metabolic disorder, arthritis, osteoporosis, central nervous systemdisease, restenosis, neurodegenerative disease, renal failure,congestive heart failure, nephrotic syndrome, cirrhosis, pulmonaryedema, hypertension, and disorders wherein the reduction of food intakeis desired, in a subject in need thereof which comprises administeringto said subject an effective amount of a compound of formula (I) asdefined hereinabove or a pharmaceutically acceptable salt thereof. Apreferred method of the immediately foregoing method is where thedisease being treated is Type I diabetes or Type II diabetes.

With the exception of the N-terminal amino acid, all abbreviations (e.g.Ala) of amino acids in this disclosure stand for the structure of—NH—CH(R)—CO—, wherein R is the side chain of an amino acid (e.g., CH₃for Ala). For the N-terminal amino acid, the abbreviation stands for thestructure of (R²R³)—N—CH(R)—CO—, wherein R is a side chain of an aminoacid and R² and R³ are as defined above, except when A⁷ is Ura, Paa orPta, in which case R² and R³ are not present since Ura, Paa and Pta areconsidered here as des-amino amino acids. Amp, β-Nal, Nle, Cha. 3-Pal,4-Pal and Aib are the abbreviations of the following α-amino acids:4-amino-phenylalanine, β-(2-naphthyl)alanine, norleucine,cyclohexylalanine, β-(3-pyridinyl)alanine, β-(4-pyridinyl)alanine andα-aminoisobutyric acid, respectively. Other amino acid definitions are:Ura is urocanic acid; Pta is (4-pyridylthio) acetic acid; Paa istrans-3-(3-pyridyl) acrylic acid; Tma-His isN,N-tetramethylamidino-histidine; N-Me-Ala is N-methyl-alanine; N-Me-Glyis N-methyl-glycine; N-Me-Glu is N-methyl-glutamic acid; Tle istert-butylglycine; Abu is α-aminobutyric acid; Tba is tert-butylalanine;Orn is ornithine; Aib is α-aminoisobutyric acid. β-Ala is P-alanine;Gaba is γ-aminobutyric acid; Ava is 5-aminovaleric acid; Ado is12-aminododecanoic acid; Aic is 2-aminoindane-2-carboxylic acid; Aun is11-aminoundecnoic acid; and Aec is4-(2-aminoethyl)-1-carboxymethyl-piperazine, represented by thestructure:

What is meant by Acc is an amino acid selected from the group of1-amino-1-cyclopropanecarboxylic acid (A3c);1-amino-1-cyclobutanecarboxylic acid (A4c);1-amino-1-cyclopentanecarboxylic acid (A5c);1-amino-1-cyclohexanecarboxylic acid (A6c);1-amino-1-cycloheptanecarboxylic acid (A7c);1-amino-1-cyclooctanecarboxylic acid (A8c); and1-amino-1-cyclononanecarboxylic acid (A9c). In the above formula,hydroxyalkyl, hydroxyphenylalkyl, and hydroxynaphthylalkyl may contain1-4 hydroxy substituents. COX⁵ stands for —C═OX⁵. Examples of —C═OX⁵include, but are not limited to, acetyl and phenylpropionyl.

What is meant by Lys(Ne-alkanoyl) is represented by the followingstructure:

What is meant by Lys(N_(ε)-alkylsulfonyl) is represented by thefollowing structure

What is meant by Lys(N_(ε)-(2-(4-alkyl-1-piperazine)-acetyl)) isrepresented by the following structure:

What is meant by Asp(1-(4-alkyl-piperazine)) is represented by thefollowing structure:

What is meant by Asp(1-alkylamino) is represented by the followingstructure:

What is meant by Lys(N_(ε)-Aec-alkanoyl) is represented by thestructure:

The variable n in the foregoing structures is 1-30. What is meant by Lys(Nε-ace-alkanoyl) is represented by the structure:

The full names for other abbreviations used herein are as follows: Bocfor t-butyloxycarbonyl, HF for hydrogen fluoride, Fm for formyl, Xan forxantbyl, Bzl for benzyl, Tos for tosyl, DNP for 2,4-dinitrophenyl, DMFfor dimethylformamide, DCM for dichloromethane, HBTU for2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate, DIEA for diisopropylethylamine, HOAc for aceticacid, TFA for trifluoroacetic acid, 2CIZ for 2-chlorobenzyloxycarbonyl,2BrZ for 2-bromobenzyloxycarbonyl, OcHex for O-cyclohexyl, Fmoc for9-fluorenylmethoxycarbonyl, HOBt for N-hydroxybenzotriazole and PAMresin for 4-hydroxymethylphenylacetamidomethyl resin.

The term “halo” encompasses fluoro, chloro, bromo and iodo.

The term “(C₁-C₃₀)hydrocarbon moiety” encompasses alkyl, alkenyl andalkynyl, and in the case of alkenyl and alkynyl there are C₂-C₃₀.

A peptide of this invention is also denoted herein by another format,e.g., (A5c⁸)hGLP-1 (7-36)NH₂ (SEQ ID NO:66), with the substituted aminoacids from the natural sequence placed between the set of parentheses(e.g., A5c⁸ for Ala⁸ in hGLP-1). The abbreviation GLP-1 meansglucagon-like peptide-1; hGLP-1 means human glucagon-like peptide-1. Thenumbers between the parentheses refer to the number of amino acidspresent in the peptide (e.g., hGLP-1 (7-36) (SEQ ID NO:1) is amino acids7 through 36 of the peptide sequence for human GLP-1). The sequence forhGLP-1(7-37) (SEQ ID NO:413) is listed in Mojsov, S., Int. J. PeptideProtein Res, 40, 1992, pp. 333-342. The designation “NH₂” inhGLP-1(7-36)NH₂ (SEQ ID NO:1) indicates that the C-terminus of thepeptide is amidated. hGLP-1(7-36) (SEQ ID NO:1) means that theC-terminus is the free acid. In hGLP-1(7-38) (SEQ ID NO:414), residuesin positions 37 and 38 are Gly and Arg, respectively.

DETAILED DESCRIPTION

The peptides of this invention can be prepared by standard solid phasepeptide synthesis. See, e.g., Stewart, J. M., et al., Solid PhaseSynthesis (Pierce Chemical Co., 2d ed. 1984). The substituents R² and R³of the above generic formula may be attached to the free amine of theN-terminal amino acid by standard methods known in the art. For example,alkyl groups, e.g., (C₁-C₃₀)alkyl, may be attached using reductivealkylation. Hydroxylalkyl groups, e.g., (C₁-C₃₀)hydroxyalkyl, may alsobe attached using reductive alkylation wherein the free hydroxy group isprotected with a t-butyl ester. Acyl groups, e.g., COE¹, may be attachedby coupling the free acid, e.g., E¹COOH, to the free amine of theN-terminal amino acid by mixing the completed resin with 3 molarequivalents of both the free acid and diisopropylcarbodiimide inmethylene chloride for one hour. If the free acid contains a freehydroxy group, e.g., p-hydroxyphenylpropionic acid, then the couplingshould be performed with an additional 3 molar equivalents of HOBT.

When R¹ is NH—X²—CH₂—CONH₂, (i.e., Z⁰═CONH₂), the synthesis of thepeptide starts with Boc-HN—X²—CH₂—COOH which is coupled to the MBHAresin. If R¹ is NH—X²—CH₂—COOH, (i.e., Z⁰═COOH) the synthesis of thepeptide starts with Boc-HN—X²—CH₂—COOH which is coupled to the PAMresin. For this particular step, 4 molar equivalents of Boc-HN—X²—COOH,HBTU and HOBt and 10 molar equivalents of DIEA are used. The couplingtime is about 8 hours.

The protected amino acid—(N-tert-butoxycarbonyl-amino)-1-cyclohexane-carboxylic acid(Boc-A6c-OH) was synthesized as follows. 19.1 g (0.133 mol) of1-amino-1-cyclohexanecarboxylic acid (Acros Organics, Fisher Scientific,Pittsburgh, Pa.) was dissolved in 200 ml of dioxane and 100 ml of water.To it was added 67 ml of 2N NaOH. The solution was cooled in anice-water bath. 32.0 g (0.147 mol) of di-tert-butyl-dicarbonate wasadded to this solution. The reaction mixture was stirred overnight atroom temperature. Dioxane was then removed under reduced pressure. 200ml of ethyl acetate was added to the remaining aqueous solution. Themixture was cooled in an ice-water bath. The pH of the aqueous later wasadjusted to about 3 by adding 4N HCl. The organic layer was separated.The aqueous later was extracted with ethyl acetate (1×100 ml). The twoorganic layers were combined and washed with water (2×150 ml), driedover anhydrous MgSO₄, filtered, and concentrated to dryness underreduced pressure. The residue was recrystallized in ethylacetate/hexanes. 9.2 g of the pure product was obtained. 29% yield.

Boc-A5c-OH was synthesized in an analogous manner to that of Boc-A6c-OH.Other protected Acc amino acids can be prepared in an analogous mannerby a person of ordinary skill in the art as enabled by the teachingsherein.

In the synthesis of a GLP-1 analogue of this invention containing A5c,A6c and/or Aib, the coupling time is 2 hrs. for these residues and theresidue immediately following them. For the synthesis of(Tma-His⁷)hGLP-1(7-36)NH₂ (SEQ ID NO:67), HBTU (2 mmol) and DIEA (1.0ml) in 4 ml DMF are used to react with the N-terminal free amine of thepeptide-resin in the last coupling reaction; the coupling time is about2 hours.

The substituents R² and R³ of the above generic formula can be attachedto the free amine of the N-terminal amino acid by standard methods knownin the art. For example, alkyl groups. e.g., (C₁-C₃₀)alkyl, can beattached using reductive alkylation. Hydroxyalkyl groups, e.g.,(C₁-C₃₀)hydroxyalkyl, can also be attached using reductive alkylationwherein the free hydroxy group is protected with a t-butyl ester. Acylgroups, e.g., COX¹, can be attached by coupling the free acid, e.g.,X¹COOH, to the free amine of the N-terminal amino acid by mixing thecompleted resin with 3 molar equivalents of both the free acid anddiisopropylcarbodiimide in methylene chloride for about one hour. If thefree acid contains a free hydroxy group, e.g., p-hydroxyphenylpropionicacid, then the coupling should be performed with an additional 3 molarequivalents of HOBT.

A compound of the present invention can be tested for activity as aGLP-1 binding compound according to the following procedure.

Cell Culture:

RIN SF rat insulinoma cells (ATCC-# CRL-2058, American Type CultureCollection, Manassas, Va.), expressing the GLP-1 receptor, were culturedin Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calfserum, and maintained at about 37° C. in a humidified atmosphere of 5%CO₂/95% air.

Radioligand Binding:

Membranes were prepared for radioligand binding studies byhomogenization of the RIN cells in 20 ml of ice-cold 50 mM Tris-HCl witha Brinkman Polytron (Westbury, N.Y.) (setting 6. 15 sec). Thehomogenates were washed twice by centrifugation (39,000 g/10 min), andthe final pellets were resuspended in 50 mM Tris-HCl, containing 2.5 mMMgCl₂, 0.1 mg/ml bacitracin (Sigma Chemical, St. Louis, Mo.), and 0.1%BSA. For assay, aliquots (0.4 ml) were incubated with 0.05 nM(¹²⁵1)GLP-1(7-36) (SEQ ID NO:415) (˜2200 Ci/mmol, New England Nuclear,Boston, Mass.), with and without 0.05 ml of unlabeled competing testpeptides. After a 100 min incubation (25° C.), the bound(¹²⁵)GLP-1(7-36) (SEQ ID NO:415) was separated from the free by rapidfiltration though GF/C filters (Brandel, Gaithersburg, Md.), which hadbeen previously soaked in 0.5% polyethyleneimine. The filters were thenwashed three times with 5 ml aliquots of ice-cold 50 mM Tris-HCl, andthe bound radioactivity trapped on the filters was counted by gammaspectrometry (Wallac LKB, Gaithersburg, Md.). Specific binding wasdefined as the total (¹²⁵I)GLP-1(7-36) (SEQ ID NO:415) bound minus thatbound in the presence of 1000 nM GLP-1(7-36) (SEQ ID NO:1) (Bachem,Torrence, Calif.).

The peptides of this invention can be provided in the form ofpharmaceutically acceptable salts. Examples of such salts include, butare not limited to, those formed with organic acids (e.g., acetic,lactic, maleic, citric, malic, ascorbic, succinic, benzoic,methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids(e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), andpolymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic,polyglycolic, or copolymers of polylactic-glycolic acids). A typicalmethod of making a salt of a peptide of the present invention is wellknown in the art and can be accomplished by standard methods of saltexchange. Accordingly, the TFA salt of a peptide of the presentinvention (the TFA salt results from the purification of the peptide byusing preparative HPLC, eluting with TFA containing buffer solutions)can be converted into another salt, such as an acetate salt bydissolving the peptide in a small amount of 0.25 N acetic acid aqueoussolution. The resulting solution is applied to a semi-prep HPLC column(Zorbax, 300 SB, C-8). The column is eluted with (1) 0.1N ammoniumacetate aqueous solution for 0.5 hrs., (2) 0.25N acetic acid aqueoussolution for 0.5 hrs. and (3) a linear gradient (20% to 100% of solutionB over 30 min.) at a flow rate of 4 ml/min (solution A is 0.25N aceticacid aqueous solution; solution B is 0.25N acetic acid inacetonitrile/water, 80:20). The fractions containing the peptide arecollected and lyophilized to dryness.

As is well known to those skilled in the art, the known and potentialuses of GLP-1 is varied and multitudinous (See, Todd, J. F., et al.,Clinical Science, 1998, 95, pp. 325-329: and Todd, J. F. et al.,European Journal of Clinical Investigation, 1997, 27, pp.533-536). Thus,the administration of the compounds of this invention for purposes ofeliciting an agonist effect can have the same effects and uses as GLP-1itself. These varied uses of GLP-1 may be summarized as follows,treatment of: Type I diabetes, Type II diabetes, obesity, glucagonomas,secretory disorders of the airway, metabolic disorder, arthritis,osteoporosis, central nervous system diseases, restenosis,neurodegenerative diseases, renal failure, congestive heart failure,nephrotic syndrome, cirrhosis, pulmonary edema, hypertension, anddisorders wherein the reduction of food intake is desired. GLP-1analogous of the present invention that elicit an antagonist effect froma subject can be used for treating the following: hypoglycemia andmalabsorption syndrome associated with gastroectomy or small bowelresection.

Accordingly, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of formula (I) in association with apharmaceutically acceptable carrier.

The dosage of active ingredient in the compositions of this inventionmay be varied: however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, on the route ofadministration, and on the duration of the treatment. In general, aneffective dosage for the activities of this invention is in the range of1×10⁻⁷ to 200 mg/kg/day, preferably 1×10⁻⁴ to 100 mg/kg/day, which canbe administered as a single dose or divided into multiple doses.

The compounds of this invention can be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous or subcutaneousinjection, or implant), nasal, vaginal, rectal, sublingual or topicalroutes of administration and can be formulated with pharmaceuticallyacceptable carriers to provide dosage forms appropriate for each routeof administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert pharmaceutically acceptablecarrier such as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, additional substances other than suchinert diluents, e.g., lubricating agents such magnesium stearate. In thecase of capsules, tablets and pills, the dosage forms may also comprisebuffering agents. Tablets and pills can additionally be prepared withenteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, the elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized by, forexample, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as coca butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

Further, a compound of this invention can be administered in a sustainedrelease composition such as those described in the following patents andpatent applications. U.S. Pat. No. 5,672,659 teaches sustained releasecompositions comprising a bioactive agent and a polyester. U.S. Pat. No.5,595,760 teaches sustained release compositions comprising a bioactiveagent in a gelable form. U.S. Pat. No. 5,821,221 teaches polymericsustained release compositions comprising a bioactive agent andchitosan. U.S. Pat. No. 5,916,883 teaches sustained release compositionscomprising a bioactive agent and cyclodextrin. U.S. application Ser. No.09/015,394 (now abandoned) filed Jan. 29, 1998, teaches absorbablesustained release compositions of a bioactive agent. U.S. ApplicationNo. 09/121,653 (now abandoned) filed Jul. 23, 1998, teaches a processfor making microparticles comprising a therapeutic agent such as apeptide in an oil-in-water process. U.S. application Ser. No. 09/131,472(now abandoned) filed Aug. 10, 1998, teaches complexes comprising atherapeutic agent such as a peptide and a phosphorylated polymer. U.S.Application No. 09/184,413 (now abandoned) filed Nov. 2, 1998, teachescomplexes comprising a therapeutic agent such as a peptide and a polymerbearing a non-polymerizable lactone. The teachings of the foregoingpatents and applications are incorporated herein by reference.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Also, all publications, patentapplications, patents and other references mentioned herein areincorporated by reference.

The following examples describe synthetic methods for making a peptideof this invention, which methods are well-known to those skilled in theart. Other methods are also known to those skilled in the art. Theexamples are provided for the purpose of illustration and is not meantto limit the scope of the present invention in any manner.

Boc-βAla-OH, Boc-D-Arg(Tos)-OH and Boc-D-Asp(OcHex) were purchased fromNova Biochem, San Diego, Calif. Boc-Aun-OH was purchased from Bachem.King of Prussia, Pa. Boc-Ava-OH and Boc-Ado-OH were purchased fromChem-Implex International, Wood Dale, Ill. Boc-Nal-OH was purchased fromSynthetech, Inc. Albany, Oreg.

EXAMPLE 1 (Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:2)

The title peptide was synthesized on an Applied Biosystems (Foster City,Calif.) model 430A peptide synthesizer which was modified to doaccelerated Boc-chemistry solid phase peptide synthesis. See Schnolzer,et al., Int. J. Peptide Protein Res., 90:180 (1992).4-methylbenz-hydrylamine (MBHA) resin (Peninsula, Belmont, Calif.) withthe substitution of 0.91 mmol/g was used. The Boc amino acids (Bachem,Calif., Torrance, Calif.; Nova Biochem., LaJolla, Calif.) were used withthe following side chain protection: Boc-Ala-OH, Boc-Arg(Tos)-OH,Boc-Asp(OcHex)-OH, Boc-Tyr(2BrZ)-OH, Boc-His(DNP)—OH, Boc-Val-OH,Boc-Leu-OH, Boc-Gly-OH, Boc-Gln-OH. Boc-Ile-OH, Boc-Lys(2CIZ)-OH,Boc-Thr(Bzl)-OH, Boc-Ser(Bzl)-OH, Boc-Phe-OH, Boc-Aib-OH,Boc-Glu(OcHex)-OH and Boc-Trp(Fm)-OH. The synthesis was carried out on a0.20 mmol scale. The Boc groups were removed by treatment with 100% TFAfor 2×1 min. Boc amino acids (2.5 mmol) were pre-activated with HBTU(2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF and were coupled withoutprior neutralization of the peptide-resin TFA salt. Coupling times were5 min. except for the Boc-Aib-OH residues and the following residues,Boc-Lys(2CIZ)-OH and Boc-His(DNP)—OH wherein the coupling times were 2hours.

At the end of the assembly of the peptide chain, the resin was treatedwith a solution of 20% mercaptoethanol/10% DIEA in DMF for 2×30 min. toremove the DNP group on the His side chain. The N-terminal Boc group wasthen removed by treatment with 100% TFA for 2×2 min. Afterneutralization of the peptide-resin with 10% DIEA in DMF (1×1 min), theformyl group on the side chain of Trp was removed by treatment with a asolution of 15% ethanolamine/15% water/70% DMF for 2×30 min. Thepeptide-resin was washed with DMF and DCM and dried under reducedpressure. The final cleavage was done by stirring the peptide-resin in10 mL of HF containing 1 mL of anisole and dithiothreitol (24 mg) at 0°C. for 75 min. HF was removed by a flow of nitrogen. The residue waswashed with ether (6×10 mL) and extracted with 4N HOAc (6×10 mL).

The peptide mixture in the aqueous extract was purified on reverse-phasepreparative high pressure liquid chromatography (HPLC) using a reversephase VYDAC(& C₁₈ column (Nest Group, Southborough, Mass.). The columnwas eluted with a linear gradient (20% to 50% of solution B over 105min.) at a flow rate of 10 mL/min (Solution A=water containing 0.1% TFA;Solution B=acetonitrile containing 0.1% of FTA). Fractions werecollected and checked on analytical HPLC. Those containing pure productwere combined and lyophilized to dryness. 135 mg of a white solid wasobtained. Purity was 98.6% based on analytical HPLC analysis.Electro-spray mass spectrometer (MS(ES))S analysis gave the molecularweight at 3339.7 (in agreement with the calculated molecular weight of3339.7).

EXAMPLE 2 ((N_(α)-HEPES-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:3)

The title compound (HEPES is(4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid)) can besynthesized as follows: after assembly of the peptide(Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:2) on MBHA resin (0.20 mmol)according to the procedure of Example 1, the peptide-resin is treatedwith 100% TFA (2×2 min.) and washed with DMF and DCM. The resin is thenneutralized with 10% DIEA in DMF for 2 min. After washing with DMF andDCM, the resin is treated with 0.23 mmol of 2-chloro-1-ethanesulfonylchloride and 0.7 mmol of DIEA in DMF for about 1 hour. The resin iswashed with DMF and DCM and treated with 1.2 mmol of2-hydroxyethylpiperazine for about 2 hours. The resin is washed with DMFand DCM and treated with different reagents ((1) 20% mercaptoethanol/10%DIEA in DMF and (2) 15% ethanolamile/15% water/70% DMF) to remove theDNP group on the His side chain and formyl group on the Trp side chainas described above before the final HF cleavage of the peptide from theresin.

EXAMPLE 3 ((N_(α)-HEPA-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:4)

The title compound (HEPA is (4-(2-hydroxyethyl)-1-piperazineacetyl)) canbe made substantially according to the procedure described in Example 2for making ((N_(α)—HEPES-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:3)except that 2-bromoacetic anhydride is used in place of2chloro-1-ethanesulfonyl chloride.

EXAMPLE 4 (Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:5)

The title compound was synthesized substantially according to theprocedure described for Example 1 using the appropriate protected aminoacids. MS (ES)=3325.7, calculated MW 3325.8, purity=99%, yield=85 mg.

The synthesis of other compounds of the present invention can beaccomplished in substantially the same manner as the procedure describedfor the synthesis of (Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:2) inExample 1 above, but using the appropriate protected amino acidsdepending on the desired peptide.

EXAMPLE 5 (Aib^(8,35), Arg^(26,24), Lys³⁶N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:6)

The Boc amino acids used were the same as those in the synthesis of(Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:2) described in Example 1 exceptthat Fmoc-Lys(Boc)-OH was used in this example. The first amino acidresidue was coupled to the resin manually on a shaker. 2.5 mmol ofFmoc-Lys(Boc)-OH was dissolved in 4 mL of 0.5N HBTU in DMF. To thesolution was added 1 mL of DIEA. The mixture was shaken for about 2 min.To the solution was then added 0.2 mmol of MBHA resin (substitution=0.91mmol/g). The mixture was shaken for about 1 hr. The resin was washedwith DMF and treated with 100% TFA for 2×2 min to remove the Bocprotecting group. The resin was washed with DMF. Myristic acid (2.5mmol) was pre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mLof DMF for 2 min and was coupled to the Fmoc-Lys-resin. The couplingtime was about 1 hr. The resin was washed with DMF and treated with 25%piperidine in DMF for 2×20 min to remove the Fmoc protecting group. Theresin was washed with DMF and transferred to the reaction vessel of thepeptide synthesizer. The following steps synthesis and purificationprocedures for the peptide were the same as those in the synthesis of(Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID NO:2) in Example 1.43.1 mg of thetitle compound were obtained as a white solid. Purity was 98% based onanalytical HPLC analysis. Electro-spray mass spectrometer analysis gavethe molecular weight at 3577.7 in agreement with the calculatedmolecular weight 3578.7.

EXAMPLE 6-8

Examples 6-8 were synthesized substantially according to the proceduredescribed for Example 5 using the appropriate protected amino acid andthe appropriate acid in place of the Myristic acid used in Example 5.

Example 6: (Aib^(8,35), Arg²⁶, Lys³⁴(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:7); Yield=89.6 mg; MS(ES)=3577.2, CalculatedMW=3578.7; Purity 96%. Example 7: (Aib ^(8,35,37), Arg^(26,34),Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:8); Yield=63.3 mg;MS(ES)=3818.7; Calculated MW=3819.5; Purity 96%. Example 8: (Aib^(8,35),Arg^(26,34), Lys³⁶(N_(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:9);Yield=57.4 mg; MS(ES)=3521.5; Calculated MW=3522.7; Purity 98%;Acid=decanoic acid.

The syntheses of the other compounds of the present invention containingLys(N_(ε)-alkanoyl) residue can be carried out in an analogous manner tothe procedure described for Example 5, (Aib^(8,35), Arg^(26,34),Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1 (7-36)NH₂ (SEQ ID NO:6).Fmoc-Lys(Boc)-OH amino acid is used for the residue ofLys(N_(ε)-alkanoyl) in the peptide, while Boc-Lys(2CIZ)-OH amino acid isused for the residue of Lys. If the Lys(N_(ε)-alkanoyl) residue is notat the C-terminus, the peptide fragment immediately prior to theLys(N_(ε)-alkanoyl) residue is assembled on the resin on the peptidesynthetizer first. The appropriate acid corresponding to the desiredalkanoyl can be purchased from Aldrich Chemical Co., Inc. Milwaukee,Wis., USA, e.g., octanoic acid, decanoic acid, lauric acid and palmiticacid.

EXAMPLE 9 (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-dodecanesulfonyl))hGLP-1(7-36)NH₂ (SEQ ID NO:10)

The Boc amino acids to be used in this synthesis are the same as thoseused in the synthesis of Example 5. The first amino acid residue iscoupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Lys(Boc)-OHis dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mLof DIEA. The mixture is shaken for about 2 min. To the solution is thenadded 0.2 mmol of MBHA resin (substitution=0.91 mmol/g). The mixture isshaken for about 1 hr. The resin is washed with DMF and treated with100% TFA for 2×2 min to remove the Boc protecting group. The resin iswashed with DMF and to it is added 0.25 mmol of 1-dodecanesulfonylchloride in 4 mL of DMF and 1 mL of DIEA. The mixture is shaken forabout 2 hrs. The resin is washed with DMF and treated with 25%piperidine in DMF for 2×20 min to remove the Fmoc protecting group. Theresin is washed with DMF and transferred to the reaction vessel of thepeptide synthesizer. The synthesis of the rest of the peptide andpurification procedures are the same as those described in Example 1.

The syntheses of other compounds of the present invention containingLys(N_(ε)-alkylsulfonyl) residue can be carried out in an analogousmanner to the procedure described in Example 9. Fmoc-Lys(Boc)-OH aminoacid is used for the residue of Lys(N_(ε)-alkylsulfonyl) in the peptide,while Boc-Lys(2CIZ)-OH amino acid is used for the residue of Lys. If theLys(N_(ε)-alkylsulfonyl) residue is not at the C-terminus, the peptidefragment immediately prior to the Lys(N_(ε)-alkylsulfonyl) residue isassembled on the resin on the peptide synthesizer first. The appropriateakylsulfonyl chloride can be obtained from Lancaster Synthesis Inc.,Windham, N.H., USA, e.g., 1-octanesulfonyl chloride, 1-decanesulfonylchloride, 1-dodecanesulfonyl chloride, 1-hexadecanesulfonyl chloride and1-octadecylsulfonyl chloride.

EXAMPLE 10 (Aib^(8,35), Arg^(26,34),Lys³⁶(N_(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)N H₂(SEQ ID NO:11)

The Boc amino acids to be used for this example are the same as thoseused in the synthesis of Example 5. The first amino acid residue iscoupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Lys(Boc)-OHis dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mLof DIEA. The mixture is shaken for about 2 min. To the solution is thenadded 0.2 mmol of MBHA (substitution=0.91 mmol/g). The mixture is shakenfor about 1 hr. The resin is washed with DMF and treated with 100% TFAfor 2×2 min to remove the Boc protecting group. The resin is washed withDMF. The 2-bromoacetic acid (2.5 mmol) is pre-activated with HBTU (2.0mmol) and DIEA (1 mL) in 4 mL of DMF for about 2 min and is added to theresin. The mixture is shaken for about 10 min and washed with DMF. Theresin is then treated with 1.2 mmol of piperazine in 4 mL of DMF forabout 2 hrs. The resin is washed with DMF and treated with 2 mmol of1-iodotetradecane for about 4 hrs. After washing with DMF, the resin istreated with 3 mmol of acetic anhydride and 1 mL of DIEA in 4 ml of DMFfor about 0.5 hr. The resin is washed with DMF and treated with 25%piperidine in DMF for 2×20 min. The resin is washed with DMF andtransferred to the reaction vessel of the peptide synthesizer tocontinue the synthesis. The remaining synthesis and purificationprocedures for the peptide are the same as the procedures described forExample 1.

The syntheses of other compounds of the present invention containingLys(N-(2-(4-alkyl-1-piperazine)-acetyl)) residue are carried out in ananalogous manner as the procedure described for the synthesis of Example10. Fmoc-Lys(Boc)-OH amino acid is used for the residue ofLys(N-(2-(4-alkyl-1-piperazine)-acetyl)) in the peptide, whileBoc-Lys(2CIZ)-OH amino acid is used for the residue of Lys. Thecorresponding iodoalkane is used for the residue ofLys(N_(ε)-(2-(4-alky-1-piperazine)-acetyl)) during the alkylation step.If the Lys(N-(2-(4-alkyl-1-piperazine)-acetyl)) residue is not at theC-terminus, the peptide fragment immediately prior to theLys(N_(ε)-(2-(4-alkyl-1-piperazine)-acetyl)) residue is assembled on theresin on the peptide synthesizer first.

EXAMPLE 11 (Aib^(8,35), Arg^(26,34) Asp³⁶(1-(4-tetradecyl-piperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:12)

The Boc amino acids to be used in this example are the same as the aminoacids used in synthesis of Example 5 except Fmoc-Asp(O-tBu)-OH is usedat position 36. The first amino acid residue is coupled to the resinmanually on a shaker. 2.5 mmol of Fmoc-Asp(O-tBu)-OH is dissolved in 4mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. Themixture is shaken for about 2 min. To the solution is then added 0.2mmol of MBHA (substitution=0.91 mmol/g) resin. The mixture is shaken forabout 1 hr. The resin is washed with DMF and treated with 100% TFA for2×15 min to remove the tBu protecting group. The resin is washed withDMF and is treated with HBTU (0.6 mmol) and DIEA (1 mL) in 4 mL of DMFfor about 15 min. 0.6 mmol of piperazine is added to the reactionmixture and the mixture is shaken for about 1 hr. The resin is washedwith DMF and treated with 3 mmol of 1-iodotetradecane for about 4 hrs.After washing with DMF, the resin is treated with 3 mmol of aceticanhydride and 1 mL of DIEA in 4 mL of DMF for about 0.5 hr. The resin iswashed with DMF and treated with 25% piperidine in DMF for 2×20 min toremove the Fmoc protecting group. The resin is washed with DMF andtransferred to the reaction vessel of the peptide synthesizer tocontinue the synthesis. The remaining synthesis and purificationprocedures for the peptide are the same as those for the synthesis ofExample 1.

The syntheses of other compounds of the present invention comprisingAsp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue arecarried out in an analogous manner as the procedure described for thesynthesis of Example 11. Fmoc-Asp(O-tBu)-OH or Fmoc-Glu(O-tBu)-OH aminoacid is used for the residue of Asp(1-(4-alkylpiperazine)) orGlu(1-(4-alkylpiperazine)) in the peptide, while Boc-Asp(OcHex)-OH orBoc-Glu(OcHex)-OH amino acid is used for the residue of Asp or Glu. Thecorresponding iodoalkane is used for the residue ofLys(Ne(2-(4-alkyl-1-piperazine)-acetyl)) during the alkylation step. Ifthe Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue isnot at the C-terminus, the peptide fragment immediately prior to theAsp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue isassembled on the resin on the peptide synthesizer first.

EXAMPLE 12 (Aib^(8,35), Arg^(26,34),Asp³⁶(1-tetradecylamino))hGLP-1(7-36)NH₂ (SEQ ID NO:13)

The Boc amino acids to be used for this example are the same as thoseused in Example 5. The first amino acid residue is coupled to the resinmanually on a shaker. 2.5 mmol of Fmoc-Asp(O-tBu)-OH is dissolved in 4mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. Themixture is shaken for about 2 min. To the solution is then added 0.2mmol of MBHA (substitution=0.91 mmol/g) resin. The mixture is shaken forabout 1 hr. The resin is washed with DMF and treated with 100% TFA for2×15 min to remove the t-Bu protecting group. The resin is washed withDMF and is treated with HBTU (0.6 mmol) and DIEA (1 mL)in 4 mL of DMFfor about 15 min. 0.6 mmol of 1-tetradecaneamine is added to thereaction mixture and the mixture is shaken for about 1 hr. The resin iswashed with DMF and treated with 25% piperidine in DMF for 2×20 min toremove the Fmoc protecting group. The resin is washed with DMF andtransferred to the reaction vessel of the peptide synthesizer tocontinue the synthesis. The remaining synthesis and purificationprocedures for the peptide of this example are the same as thosedescribed for the synthesis of Example 1.

The syntheses of other compounds of the present invention containingAsp(1-alkylamino) or Glu(1-alkylamino) residue are carried out in ananalogous manner as described for the synthesis of Example 12.Fmoc-Asp(O-tBu)-OH or Fmoc-Glu(O-tBu)-OH amino acid is used for theresidue of Asp(1-alkylamino) or Glu(1-alkylamino), respectively, in thepeptide, while Boc-Asp(OcHex)-OH or Boc-Glu(OcHex)-OH amino acid is usedfor the residue of Asp or Glu, respectively. If the Asp(1-alkylamino) orGlu(1-alkylamino) residue is not at the C-terminus, the peptide fragmentimmediately prior to the Asp(1-alkylamino) or Glu(1-alkylamino) residueis assembled on the resin on the peptide synthesizer first.

EXAMPLE 13 (Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl),β-Ala³⁷)hGLP-1(7-37)—OH (SEQ ID NO:14)

The Boc amino acids used are the same as those in the synthesis of(Aib^(8,35), Arg^(26,34), Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂(SEQ ID NO:6) (Example 5). 270 mg of Boc-β-Ala-PAM resin (Novabiochem,San Diego, Calif., substitution=0.74 mmol/g) was used. The Bioprotecting group on Boc-β-Ala-PAM resin was deblocked on a shaker with100% TFA for 2×2 min first. The remainder of the synthesis andpurification procedures were the same as that in Example 5. 83.0 mg ofthe title peptide was obtained as white solid. Purity was 99% based oilanalytical HPLC analysis. Electro-spray mass spectrometer analysis gavethe molecular weight at 3650.5 in agreement with the calculated weight3650.8.

EXAMPLE 14 (Aib^(8,35), Arg^(26,34),Lys³⁶(N_(ε)-tetradecanoyl))hGLP-1(7-36)—OH (SEQ ID NO:15)

The Boc amino acids to be used are the same as those in the synthesis of(Aib ^(8,35), Arg^(26,34), Lys³⁶ N_(ε)-tetradecanoyl))hGLP-1(7-36)NH₂(SEQ ID NO:6) (Example 5). Fmoc-Lys(Boc)-OH (2.5 mmol) is pre-activatedwith HBTU (2.0 mmol), HOBt (2.0 mmol) and DIEA (2.5 ml) in DMF (4 ml)for about 2 min. This amino acid is coupled to 235 mg of PAM resin(Chem-Impex, Wood Dale, Ill.; substitution=0.85 mmol/g) manually on ashaker. The coupling time is about 8 hrs. The remainder of the synthesisand purification procedures are the same as those in Example 5.Electro-spray mass spectrometer analysis gave the molecular weight It3579.15 in agreement with the calculated weight 3579.5.

The synthesis of other analogs of hGLP-1 (7-36)—OH (SEQ ID NO:1),hGLP-1(7-37)—OH (SEQ ID NO:413) and hGLP-1(7-38)—OH (SEQ ID NO:414) ofthe instant invention which contain Lys(N_(ε)(alkanoyl) residue can becarried out in an analogous manner according to the procedure describedfor the synthesis of Example 14. Fmoc-Lys(Boc)-OH amino acid is used forthe residue of Lys(N_(ε)(alkanoyl) in the peptide, whileBoc-Lys(2CIZ)-OH amino acid is used for the residue of Lys.

EXAMPLE 366 (Aib⁸, β-Ala³⁵, Aec³⁷)hGLP-1(7-37)NH₂ (SEQ ID NO:68)

A mixture of MBHA resin (0.2 mmol, substitution=0.91 mmol/g),Fmoc-Aec-OH (0.40g, 0.829 mmol), HBTU (1.5 mL (0.5M in DMF) and DIEA(0.5 mL) in a reaction vessel was shaken on a shaker for 4h at roomtemperature. The resin was then washed with DMF and treated with 25%piperidine in DMF for 2×20 min. The resin was washed with DMF and DCMand transferred to the reaction vessel of the peptide synthesizer tocontinue the assembly of the rest of the peptide according the proceduredescribed for Example 1. The purification procedure was also the same asthe one described in Example 1. Electro-spry mass spectrometer analysisgave the molecular weight at 3494.8 in agreement with the calculatedmolecular weight 3494.99.

Purity 93%; Yield 79.1 mg.

EXAMPLE 367 (Aib⁸, β-Ala³⁵, Aec^(37,38))hGLP-1(7-38)NH₂ (SEQ ID NO:69)

Example 367 was synthesized substantially according to the proceduredescribed for Example 366. MS(ES)=3551.7, calculated MW=3552.04; Purity97%; Yield 97.4 mg.

EXAMPLE 368 (Aib⁸, β-Ala³⁵, Aec^(37,38)) hGLP-1(7-38)NH₂ (SEQ ID NO:70)

A mixture of MBHA resin (0.2 mmol, substitution=0.91 mmol/g),Fmoc-Aec-OH (0.289g, 0.6 mmol), HBTU (1.12 mL @ 0.5M in DMF) and DIEA(0.4 mL) in a reaction vessel was shaken on a shaker for 2h at roomtemperature. The resin was then washed with DMF and treated with 30%piperidine in DMF for 2×5 min. The resin as washed with DMF. To thereaction vessel were added Fmoc-Aec-OH (0.289 g, 0.6 mmol), HBTU (1.12mL @ 0.5M in DMF) and DIEA (0.4 mL). The mixture was shaken at roomtemperature for 2 h. The resin was washed with DMF and treated with 30%piperidine in DMF for 2×15 min. The resin was washed with DMF and DCMand transferred to the reaction vessel of the peptide synthesizer tocontinue the assembly of the rest of the peptide according the proceduredescribed for Example 1. The purification procedure was also the same asthe one described in Example 1. Electro-spry, mass spectrometer analysisgave the molecular weight at 3663.9 in agreement with the calculatedmolecular weight 3664.26. Purity 100%; Yield 75.3 mg.

EXAMPLE 369 (Aib⁸, Arg^(26,34), β-Ala³⁵,Lys³⁶(N^(ε)-Aec-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:25)

A mixture of MBHA resin (0.2 mmol, substitution=0.91 mmol/g),Boc-Lys(Fmoc)-OH (1.17 g, 2.5 mmol), HBTU (4 mL @ 0.5M in DMF) and DIEA(1 mL) in a reaction vessel was shaken on a shaker at room temperaturefor 10 min. The resin was washed with DMF and treated with 25%piperidine in DMF for 2×15 min. The resin was washed with DMF. To thereaction vessel were added Fmoc-Aec-OH (0.289 g, 0.6 mmol), HBTU (1.12mL @ 0.5M in DMF) and DIEA (0.4 mL). The mixture was shaken at roomtemperature for 10 min. The resin was washed with DMF and treated with30% piperidine in DMF for 2×1 5 min. The resin was washed with DMF andtreated with a mixture of decanoic acid (431 mg, 2.5 mmol), HBTU (4 mL @(0.5M in DMF) and DIEA (1 mL) for 10 min. The resin was washed with DMFand treated with 100% TFA for 2×2 min. The resin was washed with DMF andDCM and transferred to the reaction vessel of the peptide synthesizer tocontinue the assembly of the rest of the peptide according the proceduredescribed for Example 1. The purification procedure was also the same asthe one described in Example 1. Elecro-spry mass spectrometer analysisgave the molecular weight at 3677.0 in agreement with the calculatedmolecular weight 3677.25. Purity 97.6%; Yield 44.1 mg.

The following examples can be made according to the appropriateprocedures described hereinabove.

-   Example 15: (Aib³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:71)-   Example 16: (β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:72)-   Example 17: ((N^(α)-Me-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂ (SEQ ID    NO:73)-   Example 18: ((N^(α)-Me-His)⁷, Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:74)-   Example 19: ((N^(α)-Me-His)⁷, Aib^(8,35), Arg    ^(26,34))hGLP-1(7-36)NH₂ (SEQ ID NO:75)-   Example 20: ((N^(α)-Me-His)⁷, Aib⁸, Arg^(26,34),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:76)-   Example 21: (Aib⁸, A6c³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:77)-   Example 22: (Aib⁸, A5c³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:78)-   Example 23: (Aib⁸, D-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:79)-   Example 24: (Aib^(8,35), A6c³²)hGLP-1(7-36)NH₂ (SEQ ID NO:16)-   Example 25: (Aib^(8,35), A5c³²)hGLP-1(7-36)NH₂ (SEQ ID NO:80)-   Example 26: (Aib^(8,35), Glu²³)hGLP-1(7-36)NH₂ (SEQ ID NO:17)-   Example 27: (Aib^(8,24,35))hGLP-1 (7-36)NH₂ (SEQ ID NO:18)-   Example 28: (Aib^(8,30,35))hGLP-1(7-36)NH₂ (SEQ ID NO:81)-   Example 29: (Aib ^(8,25,35))hGLP-1(7-36)NH₂ (SEQ ID NO:82)-   Example 30: (Aib^(8,35) A6c^(16,20))hGLP-1(7-36)NH₂ (SEQ ID NO:83)-   Example 31: (Aib^(8,35), A6c^(16,29,32))hGLP-1(7-36)NH₂ (SEQ ID    NO:84)-   Example 32: (Aib^(8,35) A6c^(20,32))hGLP-1(7-36)NH₂ (SEQ ID NO:85)-   Example 33: (Aib^(8,35), A6c²⁰)hGLP-1(7-36)NR₂ (SEQ ID NO:86)-   Example 34: (Aib^(8,35), Lys²⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:87)-   Example 33: (Aib^(8,35), A6c²⁰)hGLP-1(7-36)NH₂ (SEQ ID NO:88)-   Example 36: (Aib^(8,35), A6c^(29.32))hGLP-1(7-36)NH₂ (SEQ ID NO:89)-   Example 37: (Aib^(8,24,35) A6c^(29,32))hGLP-1(7-36)NH₂ (SEQ ID    NO:90)-   Example 38: (Aib^(8,35), A6c¹²)hGLP-1(7-36)NH₂ (SEQ ID NO:91)-   Example 39: (Aib^(8,35), Cha²⁰)hGLP-1(7-36)NH₂ (SEQ ID NO:92)-   Example 40: (Aib^(8,35), A6c³³)hGLP-1(7-36)NH₂ (SEQ ID NO:93)-   Example 41: (Aib^(8,35), A6c^(20,32))hGLP-1(7-36)NH₂ (SEQ ID NO:85)-   Example 42: (Aib⁸, A6c^(16,20), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:94)-   Example 43: (Aib^(8,35), β-Ala²²)hGLP-1(7-36)NH₂ (SEQ ID NO:95)-   Example 44: (Aib^(8,22,35))hGLP-1(7-36)NH₂ (SEQ ID NO:96)-   Example 45: (Aib^(8,35) Glu²³ A6c³²)hGLP-1(7-36)NH₂ (SEQ ID NO:89)-   Example 46: (Aib^(8,24,35) Glu²³ A6c³²)hGLP-1(736)NH₂ (SEQ ID NO:97)-   Example 47: (Aib^(8,24,25,35), Glu²³, A6c³²)hGLP-1(7-36)N₂ (SEQ ID    NO:98)-   Example 48: (Aib^(8,24,25,35), A6c^(16,20,32),    Glu²³,)hGLP-1(7-36)NH₂ (SEQ ID NO:99)-   Example 49: (Aib⁸, A6c³², β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:100)-   Example 50: (Aib⁸, A5c³², β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:101)-   Example 51: (Aib⁸, Glu²³, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:20)-   Example 52: (Aib^(8,24), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:102)-   Example 53: (Aib^(8,30), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:103)-   Example 54: (Aib^(8,25), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:104)-   Example 55: (Aib⁸, A6c^(16,20,) β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:94)-   Example 56: (Aib⁸, A6c^(20,32), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:105)-   Example 57: (Aib⁸, A6c²⁰, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:106)-   Example 58: (Aib⁸, A6c²⁰, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:107)-   Example 59: (Aib⁸, Lys²⁵, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:108)-   Example 60: (Aib^(8,24), A6c²⁰, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:108)-   Example 61: (Aib⁸, A6C^(29,32), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:110)-   Example 62: (Aib^(8,24), A6c^(29,32), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ    ID NO:111)-   Example 63: (Aib⁸, A6c¹², β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:112)-   Example 64: (Aib⁸, Cha²⁰, β-Ala³⁵)hGLP-1(7-36)NR₂ (SEQ ID NO:113)-   Example 65: (Aib⁸, A6c³³, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:114)-   Example 66: (Aib⁸ A6c^(20,32), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:106)-   Example 67: (Aib⁸, β-Ala^(22,35))hGLP-1(7-36)NH₂ (SEQ ID NO:115)-   Example 66: (Aib^(8,22), β-Ala³⁵)hGLP-1(7-36)N N₂ (SEQ ID NO:116)-   Example 69: (Aib⁸, Glu²³ A6c³², β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:117)-   Example 70: (Aib^(8,24), Glu²³, A6c³², β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ    ID NO:118)-   Example 71: (Aib^(8,24), Glu²³, A6c³², Lys³⁴(N_(ε)-octanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:119)-   Example 72: (Aib^(8,24,25), Glu²³, A6c³², β-Ala³⁵)hGLP-1(7-36)NH₂    (SEQ ID NO:120)-   Example 73: (Aib^(8,24,25), A6c^(16,20,32) Glu²³ , β-Ala    ³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:121)-   Example 74: (Aib^(8,35), D-Arg³⁶)hGLP-1(7-36)NH₂ (SEQ ID NO:122)-   Example 75: (Aib^(8,35), D-Lys³⁶)hGLP-1 (7-36)NH₂ (SEQ ID NO:123)-   Example 76: (Aib⁸, β-Ala³⁵, D-Arg³⁶)hGLP-1(7-36)NH₂ (SEQ ID NO:124)-   Example 77: (Aib⁸, β-Ala³⁵, D-Lys³⁶)hGLP-1(7-36)NH₂ (SEQ ID NO:125)-   Example 78: (Aib^(8,35) Arg^(26,34))hGLP-1(7-36)NH₂ (SEQ ID NO:21)-   Example 79: (Aib⁸, Arg^(226,34) β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:126)-   Example 80: (Aib^(8,35) Arg^(25,26,34))hGLP-1(7-36)NH₂ (SEQ ID    NO:127)-   Example 81: (Aib 8, Arg^(25,26,34), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:128)-   Example 82: (Aib⁸, Arg^(26,34), β-Ala³⁶,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)OH (SEQ ID NO:129)-   Example 83: (Aib^(8,35), Arg^(26,34),    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-37)OH (SEQ ID NO:130)-   Example 84: (Aib^(8,35,37), Arg^(26,34),    Lys³⁶N^(ε)-tetradecanoyl))hGLP-1(7-37)0H (SEQ ID NO:131)-   Example 84: (Aib^(8,35,37), Arg^(26,34),    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-37)OH (SEQ ID NO:131)-   Example 85: (Aib^(8,35), Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl),    D-Ala³⁷)hGLP-1(7-37)OH (SEQ ID NO:132)-   Example 86: (Aib^(8,35,37), Arg^(26,34),    Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)OH (SEQ ID NO:133)-   Example 87: (Aib^(8,35), Arg^(26,34), β-Ala³⁷,    Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)OH (SEQ ID NO:134)-   Example 88: (Aib^(8,35), Arg^(26,34)    Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)OH(SEQ ID NO:135)-   Example 89: (Aib⁸, Arg^(26,34), Lys³⁶ (N^(ε)-tetradecanoyl),    β-Ala³⁷)hGLP-1(7-37)OH (SEQ ID NO:136)-   Example 90: (Aib^(8,37), Arg^(26,34),    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-37)OH(SEQ ID NO:137)-   Example 91: (Aib^(8,35), Arg^(26,34), Ado³⁷)hGLP-[(7-37)OH (SEQ ID    NO:138)-   Example 92: (Aib^(8,35) Arg^(26,34) Ado³⁷)hGLP-1(7-37)NH₂ (SEQ ID    NO:139)-   Example 93: (Aib⁸, Arg^(26,34), Lys³⁶(N^(ε)-tetradecanoyl),    D-Ala³⁷)hGLP-1(7-37)OH (SEQ ID NO 140)-   Example 94: (Aib^(8,37), Arg^(26,34), Lys^(38l (N)    ^(ε)-tetradecanoyl))hGLP-1(7-38)OH (SEQ ID NO:141)-   Example 95: (Aib⁸, Arg^(26,34), Ala³⁷,    Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)OH (SEQ ID NO:142)-   Example 96: (Aib^(8,35), Lys²⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ    ID NO:143)-   Example 97: (Aib^(8,35), Lys²⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂    (SEQ ID NO:144)-   Example 98: (Aib^(8,35), Lys²⁶ (N^(ε)-hexadecanoyl))hGLP-1 (7-36)NH₂    (SEQ ID NO:145)-   Example 99: (Aib⁸, Lys²⁶ (N^(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂    (SEQ ID NO:146)-   Example 100: (Aib⁸, Lys²⁶(N^(ε)-tetradecanoyl),    β-Ala³⁵)]GLP-1(7-36)NH₂ (SEQ ID NO:147)-   Example 101: (Aib⁸, Lys²⁶(N^(ε)-hexadecanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:148)-   Example 102: (Aib^(8,35), Lys²⁶ (N^(ε)-octanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:149)-   Example 103: (Aib^(8,35), Lys²⁶(N^(ε)-tetradecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:150)-   Example 104: (Aib^(8,35), Lys²⁶ (N^(ε)-hexadecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:151)-   Example 105: (Aib^(8,35), Lys²⁶(N^(ε)-decanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:152)-   Example 106: (Aib^(8,35), Lys²⁵, Lys²⁶(N^(ε)-octanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:153)-   Example 107: (Aib ^(8,35), Lys²⁵, Lys²⁶(N^(ε)-tetradecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:154)-   Example 108: (Aib^(8,35), Lys²⁵, Lys²⁶(N^(ε)-hexadecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:155)-   Example 109: (Aib^(8,35) Arg^(25,34),    Lys²⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:156)-   Example 110: (Aib^(8,35) Arg^(25,34),    Lys²⁶(N^(ε)-tetradecanoyl))hGLP-1 (7-36)NH₂ (SEQ ID NO:157)-   Example 111: (Aib^(8,35), Arg^(25,34), Lys²⁶    (N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:158)-   Example 112: (Aib^(8,35) Arg^(25,34)    Lys²⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:159)-   Example 113: (Aib⁸, Lys²⁶(N^(ε)-octanoyl), Arg³⁴,    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:160)-   Example 1114: (Aib⁸, Lys²⁶(N^(ε)-tetradecanoyl), Arg³⁴,    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:161)-   Example 115: (Aib⁸, Lys²⁶(N^(ε)-hexadecanoyl), Arg³⁴,    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:162)-   Example 116: (Aib⁸, Lys²⁶ (N^(ε)-decanoyl), Arg³⁴, β-Ala³⁵)hGLP-1    (7-36)NH₂ (SEQ ID NO:163)-   Example 117: (Aib^(8,35), Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ    ID NO:164)-   Example 118: (Aib^(8,35), Lys³⁴(N-tetradecanoyl))hGLP-1(7-36)NH₂    (SEQ ID NO:165)-   Example 119: (Aib^(8,35), Lys³⁴ (N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂    (SEQ ID NO:166)-   Example 120: (Aib^(8,35), Arg²⁶,    Lys³⁴(N^(ε)-octanoyl))hGLP-1(736)NH₂ (SEQ ID NO:167)-   Example 121: (Aib^(8,35), Arg²⁶,    Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7736)NH₂ (SEQ ID NO:168)-   Example 122: (Aib^(8,35), Arg²⁶,    Lys³⁴(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:169)-   Example 123: (Aib^(8,35), Arg^(25.26) Lys³⁴    (N^(ε)-octanoyl))hGLP-1(736)NH₂(SEQ ID NO 170)-   Example 124: (Aib^(8,35), Arg^(25,26)    Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO: 71)-   Example 125: (Aib^(8,35), Arg^(25,26),    Lys³⁴(N^(ε)-hexadecanoyl))hGLP-11(7736)NH₂ (SEQ ID NO:172)-   Example 126: (Aib^(8,35), Arg^(25,26),    Lys³⁴(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:173)-   Example 127: (Aib^(8,35), Lys²⁵, Arg²⁶,    Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:174)-   Example 128: (Aib^(8,35) Lys²⁵, Arg²⁶,    Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:175)-   Example 129: (Aib^(8,35), Lys²⁵, Arg²⁶    Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1 (7-36)NH₂ (SEQ ID NO:176)-   Example 130: (Aib^(8,35), Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ    ID NO:177)-   Example 131: (Aib^(8,35), Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂    (SEQ ID NO:178)-   Example 132: (Aib^(8,35), Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1 (7-36)NH₂    (SEQ ID NO:179)-   Example 133: (Aib^(8,35), Arg²⁶,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:180)-   Example 134: (Aib^(8,35), Arg¹⁶,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:181)-   Example 135: (Aib^(8,35), Arg²⁶,    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:182)-   Example 136: (Aib^(8,35), Arg^(26,34)    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:183)-   Example 137: (Aib^(8,35), Arg^(26,34),    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:184)-   Example 138: (Aib^(8,35), Arg^(26,34),    Lys³⁸(N^(ε)-octanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:185)-   Example 139: (Aib^(8,35), Arg^(26,34),    Lys³⁸(N^(ε)-decanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:186)-   Example 140: (Aib^(8,35) Arg^(26,34) Lys³⁸    N^(ε)-tetradecanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:187)-   Example 141: (Aib^(8,35), Arg^(26,34),    Lys³⁸(N^(ε)-hexadecanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:188)-   Example 142: (Aib^(8,35,37), Arg^(25,26,34),    Lys³⁸(N^(ε)-octanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:189)-   Example 143 (Aib^(8,35,37), Arg^(26,26,34)    Lys³⁸(N^(ε)-decanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:190)-   Example 144: (Aib^(8,35,37) Arg^(25,26,34)    Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(738)NH₂(SEQ ID NO:191)-   Example 145: (Aib^(8,35,37), Arg^(25,26,34),    Lys³⁸(N^(ε)-hexadecanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:191)-   Example 146: (Aib^(8,35,37), Arg^(26,34),    Lys³⁸(N^(ε)-octanoyl))hGLP-1(7-38)NH₂(SEQ ID NO:193)-   Example 147: (Aib^(8,35,37), Arg^(26,34),    Lys³⁸(N^(ε)-decanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:194)-   Example 148: (Aib^(8,35,37), Arg^(26,34),    Lys³⁸(N^(ε)-hexadecanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:195)-   Example 149: (Aib^(8,35,37), Arg^(25,26),    Lys³⁸(N^(ε)-octanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:189)-   Example 150: (Aib^(8,35,37), Arg^(25,26,34),    Lys³⁸(N^(ε)-decanoyl))hGLP-1(7-38)NH₂ (SEQ ID NO:190)-   Example 151: (Aib^(8,35,37), Arg^(25,26,34),    Lys³⁸(N^(ε)-tetradecanoyl))hGLP-1(7-38)N H₂ (SEQ ID NO:191)-   Example 152: (Aib^(8,35,37), Arg^(25,26,34),    Lys³⁸(N^(ε)-hexadecanoyl))hGLP-1(7-38)NH₂(SEQ ID NO:192)-   Example 153: (Aib^(8,35) Lys²⁵ Arg^(26,34)    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:196)-   Example 154: (Aib^(8,35), Lys²⁵, Arg^(26,34), Lys³⁶    (N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:197)-   Example 155: (Aib^(8,35), Lys²⁵, Arg^(26,34),    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂(SEQ ID NO:198)-   Example 156: (Aib^(8,35), Arg^(25,26,34),    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:199)-   Example 157: (Aib^(8,35), Arg^(25,26,34),    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:200)-   Example 158: (Aib^(8,35), Arg^(25,26,34),    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:201)-   Example 159: (Aib^(8,35), Arg^(25,26,34),    Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:202)-   Example 160: (Aib⁸, Lys³⁴(N^(ε)-octanoyl), β-Ala³⁵)hGLP-1(7-36)NH₂    (SEQ ID NO:203)-   Example 161: (Aib⁸, Lys³⁴(N^(ε)-tetradecanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:204)-   Example 162: (Aib⁸, Lys³⁴(N^(ε)-hexadecanoyl),    13-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:205)-   Example 163: (Aib⁸, A6c³², Lys³⁴(N_(ε)-octanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:206)-   Example 164: (Aib⁸, Glu²³, Lys³⁴ (N^(ε)-octanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:207)-   Example 165: (Aib⁸, Glu²³, A6c³², Lys³⁴ (N^(ε)-octanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:208)-   Example 166: (Aib⁸, Arg²⁶, Lys³⁴(N^(ε)-octanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:209)-   Example 167: (Aib⁸, Arg²⁶, Lys³⁴ (N^(ε)-tetradecanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:210)-   Example 168: (Aib⁸, Arg²⁶, Lys³⁴(N^(ε)-hexadecanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:211)-   Example 169: (Aib⁸, Arg²⁶, Lys³⁴(N^(ε)-decanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:212)-   Example 170: (Aib⁸, Arg^(25,26), Lys³⁴(N^(ε)-octanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:213)-   Example 171: (Aib⁸, Arg^(25,26), Lys³⁴(^(ε)-tetradecanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:214)-   Example 172: (Aib⁸, Arg^(25,26), Lys³⁴(N^(ε)-hexadecanoyl),    β-Ala³⁵)hGLP-1 (7-36)NH₂ (SEQ ID NO:215)-   Example 173: (Aib⁸, Arg^(25,26), Lys³⁴(N^(ε)-decanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:216)-   Example 174: (Aib⁸, Lys²⁵, Arg²⁶, Lys³⁴(N^(ε)-octanoyl), β-Ala    ³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:217)-   Example 175: (Aib⁸, Lys²⁵, Arg²⁶, Lys³⁴(N^(ε)-tetradecanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:218)-   Example 176: (Aib⁸, Lys²⁵, Arg²⁶, Lys³⁴(N^(ε)-hexadecanoyl),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:219)-   Example 177: (Aib⁸, β-Ala³⁵, Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂    (SEQ ID NO:220)-   Example 178: (Aib⁸, β-Ala³⁵,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:221)-   Example 179: (Aib⁸, β-Ala³⁵,    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:222)-   Example 180: (Aib⁸, Arg²⁶, β-Ala³⁵,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:223)-   Example 181: (Aib⁸, Arg²⁶, β-Ala³⁵,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:224)-   Example 182: (Aib⁸, Arg²⁶, β-Ala³⁵, Lys³⁶    (N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:225)-   Example 183: (Aib⁸, Arg^(26,34), β-Ala³⁵,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:226)-   Example 184: (Aib⁸, Arg^(26,34), β-Ala³⁵,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:227)-   Example 185: (Aib⁸, Arg^(26,34), β-Ala³⁵,    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:228)-   Example 186: (Aib⁸, Arg^(26,34), β-Ala³⁵, Lys³⁶    (N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:229)-   Example 187: (Aib⁸, Lys²⁵, Arg^(26,34), β-Ala³⁵,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:230)-   Example 188: (Aib⁸, Lys²⁵, Arg^(26,34), Lys³⁶ (N^(ε)-tetradecanoyl),    P3-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:231)-   Example 189: (Aib⁸, Lys²⁵, Arg^(26,34), β-Ala³⁵, Lys³⁶    (N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₇ (SEQ ID NO:232)-   Example 190: (Aib⁸, Arg^(25,26,34), β-Ala³⁵,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:233)-   Example 191: (Aib⁸, Arg^(25,26,34), β-Ala³⁵,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:234)-   Example 192: (Aib⁸, Arg^(25,26,34), β-Ala³⁵,    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:235)-   Example 193: (Aib⁸, Arg^(25,26,34), β-Ala³⁵,    Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:236)-   Example 194: (Aib^(8,35), Lys²⁶(N^(ε)-octanoyl), A6c³²,    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:237)-   Example 195: (Aib^(8,35), Lys²⁶(N^(ε)-tetradecanoyl), A6c³²,    Arg)hGLP-1(7-36)NH₂ (SEQ ID NO:238)-   Example 196: (Aib^(8,35), Lys²⁶(N^(ε)-hexadecanoyl), A6c³²,    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:239)-   Example 197: (Aib^(8,35), A6c³², Lys³⁴    (N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:240)-   Example 198: (Aib^(8,35), A6c³²,    Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:241)-   Example 199: (Aib^(8,35), A6c³²,    Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:242)-   Example 200: (Aib^(8,35), Arg²⁶, A6c³²,    Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:243)-   Example 201: (Aib^(8,35) Arg, A6c³², Lys³⁴    (N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:244)-   Example 202: (Aib^(8,35), A6c³²,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:245)-   Example 203: (Aib^(8,35), A6c³²,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:246)-   Example 204: (Aib^(8,35), A6c³²,    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂(SEQ ID NO:247)-   Example 205: (Aib^(8,35), Arg²⁶, A6c³²,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:248)-   Example 206: (Aib^(8,35), Arg²⁶, A6c³²,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:249)-   Example 207: (Aib^(8,35), Arg²⁶, A6c³²,    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1 (7-36)NH₂ (SEQ ID NO:250)-   Example 208: (Aib^(8,35), Arg^(26,34) A6c³²    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:251)-   Example 209: (Aib^(3,35), Arg^(26,34), A6c³²    Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:252)-   Example 210: (Aib^(8,35), Arg^(26,34), A6c³²    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:253)-   Example 211 (Aib^(8,35), Arg^(26,34), A6c³² Lys³⁶    (N^(ε)-hexadecanoyl))hGLP-1(7-6)NH₂ (SEQ ID NO:254)-   Example 211: (Aib^(8,35), Arg^(26,34), A6c³² Ly    (N^(ε)-hexadecanoyl))hGLP)-(7-36)NH₂(SEQ ID NO:254)-   Example 212: (Aib^(8,24,35), Lys²⁶(N^(ε)-octanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:255)-   Example 213: (Aib^(824,35), Lys²⁶ (N^(ε)-tetradecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:256)-   Example 214: (Aib^(8,24,35), Lys²⁶(N^(ε)-hexadecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:257)-   Example 215: (Aib^(8,24,35), Arg²⁶,    Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:258)-   Example 216: (Aib^(8,24,35), Arg²⁶,    Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(736)NH₂ (SEQ ID NO:259)-   Example 217: (Aib ^(8,24,35), Arg²⁶,    Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1 (7-36)NH₂ (SEQ ID NO:260)-   Example 218: (Aib^(8,24,35) Arg^(26,34),    Lys³(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:261)-   Example 219: (Aib^(8,24,35), Arg^(26,34),    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:262)-   Example 220: (Aib^(8,24,35), Arg^(26.34),    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:263)-   Example 221: (Aib^(8,24,35) Glu²³, A6c³²,    Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:264)-   Example 222: (Aib^(8,35), Glu²³, Lys²⁶ N^(ε)-octanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:265)-   Example 223: (Aib^(8,35), Glu ²³ Lys²⁶(N^(ε)-tetradecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:266)-   Example 224: (Aib^(8,35), Glu²³, Lys²⁶ (N^(ε)-hexadecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:267)-   Example 225: (Aib^(8,35), Glu²³, Lys³⁴    (N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:268)-   Example 226: (Aib^(8,35), Glu²³, A6c³², Lys³⁴    (N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:269)-   Example 227: (Aib^(8,35), Glu²³, Arg²⁶,    Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:270)-   Example 228: (Aib^(8,35), Glu²³, Arg²⁶,    Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:271)-   Example 229: (Aib^(8,35), Glu²³, Arg²⁶,    Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:272)-   Example 230: (Aib^(8,35), Glu²³,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:273)-   Example 231: (Aib^(8,35), Glu²³,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:274)-   Example 232: (Aib^(8,35), Glu²³, Lys³⁶ (N^(ε)-hexadecanoyl))hGLP-1    (7-36)NH₂ (SEQ ID NO:275)-   Example 233: (Aib^(8,35), Glu²³, Arg^(26,34), Lys³⁶    (N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:276)-   Example 234: (Aib^(8,35) Glu²³ Arg^(26,34)    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:277)-   Example 235: (Aib^(8,35), Glu²³ Arg^(26,34),    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:278)-   Example 236: (Aib^(8,30,35), Lys²⁶(N^(ε)-octanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:279)-   Example 237: (Aib^(8,30,35), Lys²⁶ (N^(ε)-tetradecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:280)-   Example 238: (Aib^(8,30,35), Lys²⁶ (N^(ε)-hexadecanoyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:281)-   Example 239: (Aib^(8,30,35), Arg²⁶,    Lys³⁴(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:282)-   Example 240: (Aib^(8,30,35), Arg²⁶,    Lys³⁴(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:283)-   Example 241: (Aib^(8,30,35), Arg²⁶,    Lys³⁴(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:284)-   Example 242: (Aib^(8,30,35), Arg^(26,34),    Lys³⁶(N^(ε)-6-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:285)-   Example 243: (Aib^(8,30,35), Arg^(26,34),    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:286)-   Example 244: (Aib^(8,30,35) Arg^(26,34)    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:287)-   Example 245: (Aib^(8,35), Glu²³, A6c³²,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:288)-   Example 246: (Aib^(8,35), Glu²³, A6c³²,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:289)-   Example 247: (Aib^(8,35), Glu²³, A6c³², Lys³⁶    (N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:290)-   Example 248: (Aib ^(8,35), Glu²³, Arg^(26,34), A6c³²,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:291)-   Example 249: (Aib^(8,35), Glu²³ Arg^(26,34) A6c³²,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:292)-   Example 250: (Aib^(8,35), Glu³⁵Arg^(26,34) A6c³²    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:293)-   Example 251: (Aib^(8,24,35), Glu²³, Arg^(26,34), A6c³²,    Lys³⁶(N^(ε)-octanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:294)-   Example 252: (Aib^(8,24,35), Glu²³, Arg^(26,34), A6c³²,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:295)-   Example 253: (Aib^(8,24,35), Glu²³, Arg^(26,34), A6c³²,    Lys³⁶(N^(ε)-hexadecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:296)-   Example 254: (Aib^(8,24,30,35), Glu²³, Arg^(26,34), A6c³²,    Lys³⁶(N^(ε)-octanoyl))hGLP-1 (7-36)NH₂ (SEQ ID NO:297)-   Example 255: (Aib ^(24,30,35), Glu²³, Arg^(26,34) A6c³²,    Lys³⁶(N^(ε)-tetradecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:298)-   Example 256: (Aib^(8,24,30,35), Glu²³, Arg^(26,34), A6c³²,    Lys³⁶(N^(ε)-hexadecanoyl)hGLP-1(7-36)NH₁ (SEQ ID NO:299)-   Example 257: ((N^(α)-HEPES-His)⁷, Aib³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:300)-   Example 258: ((N^(α)-HEPES-His)⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:301)-   Example 259: ((N^(α)-HEPES-His)⁷, Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ    ID NO:302)-   Example 260: ((N^(α)-HEPA-His)⁷, Aib³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:303)-   Example 261: ((N^(α)-HEPA-His)⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:304)-   Example 262: ((N^(α)-HEPA-His)⁷, Aib⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ    ID NO:305)-   Example 263: ((N^(α)-tetradecanoyl-His)⁷, Aib³⁵)hGLP-1(7-36)NH₂ (SEQ    ID NO:306)-   Example 264: ((N^(α)-tetradecanoyl-His)⁷, β-Ala³⁵)hGLP-1(7-36)NH₂    (SEQ ID NO:307)-   Example 265: ((N^(α)-tetradecanoyl-His)⁷, Aib^(8,35))hGLP-1(7-36)NH₂    (SEQ ID NO:308)-   Example 266: ((N^(α)-tetradecanoyl-His)⁷, Aib⁸,    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:309)-   Example 267: (N^(α)-tetradecanoyl-His)⁷, Arg^(26,34),    Aib³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:310)-   Example 268: ((N^(α)-tetradecanoyl-His)⁷, Arg^(26,34),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:311)-   Example 269: ((N^(α)-tetradecanoyl-His)⁷, Aib^(8,35),    Arg^(26,34))hGLP-1 (7-36)NH₂ (SEQ ID NO:312)-   Example 270: ((N^(α)-tetradecanoyl-His)⁷, Aib⁸,    Arg^(26,34,35))hGLP-1(7-36)NH₂ (SEQ ID NO:313)-   Example 271: ((N^(α)-tetradecanoyl-His)⁷, Arg^(25,26,34),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:314)-   Example 272: ((N^(α)-tetradecanoyl-His)⁷, Aib^(8,35),    Arg^(25,26,34))hGLP-1(7-36)NH₂ (SEQ ID NO:315)-   Example 273: ((N^(α)-tetradecanoyl-His)⁷, Aib⁸, Arg^(25,26,34),    β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:316)-   Example 274: (Aib ^(8,35), Lys²⁶(N^(α)-octanesulfonyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:317)-   Example 275: (Aib^(8,35), Lys²⁶ (N-dodecanesulfonyl), Arg³⁴)hGLP-1    (7-36)NH₂ (SEQ ID NO:318)-   Example 276: (Aib^(8,35), Lys²⁶(N^(α)-hexadecanesulfonyl),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:319)-   Example 277: (Aib^(8,35), Arg²⁶,    Lys³⁴(N^(ε)-octanesulfonyl))hGLP-1(7-36)NH₂ (SEQ ID NO:320)-   Example 278: (Aib^(8,35), Arg²⁶,    Lys³⁴(dodecanesulfonyl))hGLP-1(7-36)NH₂ (SEQ ID NO:21-   Example 279: (Aib^(8,35), Arg²⁶,    Lys³⁴(N^(ε)-hexadecanesulfonyl))hGLP-1(736)NH₂ (SEQ ID NO:322)-   Example 280: (Aib^(8,35), Arg^(26,34),    Lys³⁶(N^(ε)-octanesulfonyl))hGLP-1(7-36)NH₂ (SEQ ID NO:323)-   Example 281: (Aib^(8,35) Arg^(26,34)    Lys³⁶(N^(ε)-hexadecanesulfonyl))hGLP-1(7-36)NH₂ (SEQ ID NO:324)-   Example 282: (Aib^(8,35), Asp²⁶(1-(4-decylpiperazine)), Arg³⁴)hGLP-1    (7-36)NH₂ (SEQ ID NO:325)-   Example 283: (Aib^(8,35), Asp²6(1-(4-dodecylpiperazine)),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:326)-   Example 284: (Aib^(8,35), Asp²⁶(1-(4-tetradecylpiperazine)),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:327)-   Example 285: (Aib^(8,35), Asp²⁶(1-(4-hexadecylpiperazine)),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:328)-   Example 286: (Aib^(8,35), Arg²⁶,    Asp³⁴(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:329)-   Example 287: (Aib^(8,35), Arg²⁶    Asp³⁴(2-(4-dodecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:330)-   Example 288: (Aib^(8,35), Arg²⁶,    Asp³⁴(1-(4-tetradecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:331)-   Example 289: (Aib^(8,35), Arg²⁶,    Asp³⁴(1-(4-hexadecylpiperazine)))hGLP-1 (7-36)NH₂ (SEQ ID NO:332)-   Example 290: (Aib^(8,35), Arg^(26,34),    Asp³⁶(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:333)-   Example 291: (Aib^(8,35), Arg^(26,34)    Asp³⁶(1-(4-dodecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:334)-   Example 292: (Aib^(8,35), Arg^(26,34),    Asp³⁶(1-(4-hexadecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:335)-   Example 293: (Aib^(8,35), Arg^(26,34) Asp³⁸    ⁽1-(4-decylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:336)-   Example 294: (Aib^(8,35), Arg^(26,34),    Asp³⁸(1-(4-dodecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:337)-   Example 295: (Aib^(8,35), Arg^(26,34),    Asp³⁸(1-(4-tetradecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:338)-   Example 296: (Aib^(8,35), Arg^(26,34),    Asp³⁸(1-(4-hexadecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:339)-   Example 297: (Aib^(8,35,37), Arg^(26,34),    Asp³⁸(1-(4-decylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:340)-   Example 298: (Aib^(8,35,37), Arg^(26,34),    Asp³⁸(1-(4-dodecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:341)-   Example 299: (Aib^(8,35,37), Arg^(26,34),    Asp³⁸(1-(4-tetradecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:342)-   Example 300: (Aib^(8,35,37) Arg^(26,34),    Asp³⁸(1-(4-hexadecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:343)-   Example 301: (Aib^(8,35), Arg ^(25,34),    Asp²⁶(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:344)-   Example 302: (Aib^(8,35), Arg^(25,34),    Asp²⁶(1-(4-dodecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:345)-   Example 303: (Aib^(8,35), Arg^(25,34),    Asp²⁶(1-(4-tetradecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:346)-   Example 304: (Aib^(8,35), Arg^(25,34),    Asp²⁶(1-(4-hexadecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:347)-   Example 305: (Aib^(8,35), Arg^(25,26),    Asp³⁴(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:348)-   Example 306: (Aib^(8,35), Arg^(25,26),    Asp³⁴(1-(4-dodecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:349)-   Example 307: (Aib^(8,35), Arg^(25,26),    Asp³⁴(1-(4-tetradecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:350)-   Example 308: (Aib^(8,35), Arg^(25,26),    Asp³⁴(1-(4-hexadecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:351)-   Example 309: (Aib^(8,35), Arg^(25,26,34),    Asp³⁶(1-(4-decylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:352)-   Example 310: (Aib^(8,35) Arg^(25,26,34)    Asp³⁶(1-(4-dodecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:353)-   Example 311: (Aib^(8,35), Arg^(25,26,34),    Asp³⁶(1-(4-tetradecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:354)-   Example 312: (Aib^(8,35), Arg^(25,26,34),    Asp³⁶(1-(4-hexadecylpiperazine)))hGLP-1(7-36)NH₂ (SEQ ID NO:355)-   Example 313: (Aib^(8,35), Arg^(25,26,34)    Asp³⁸(1-(4-decylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:356)-   Example 314: (Aib^(8,35), Arg^(25,26,34)    Asp³⁸(1-(4-dodecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:357)-   Example 315: (Aib^(8,35), Arg^(25,26,34),    Asp³⁸(1-(4-tetradecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:358)-   Example 316: (Aib^(8,35), Arg^(25,26,34),    Asp³⁸(1-(4-hexadecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:359)-   Example 317: (Aib^(8,35,37), Arg^(25,26,34)    Asp³⁸(1-(4-decylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:360)-   Example 318: (Aib^(8,35,37), Arg^(25,26,34),    Asp³⁸(1-(4-dodecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:361)-   Example 319: (Aib^(8,35,37), Arg^(25,26,34)    Asp³⁸(1-(4-tetradecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:362)-   Example 320: (Aib^(8,35,37), Arg^(25,26,34),    Asp³⁸(1-(4-hexadecylpiperazine)))hGLP-1(7-38)NH₂ (SEQ ID NO:363)-   Example 321: (Aib^(8,35), Arg^(26,34), Glu³⁶(1-dodecylamino))hGLP-1    (7-36)NH, (SEQ ID NO:364)-   Example 322: (Aib^(8,35), Glu²⁶(1-dodecylamino),    Arg³⁴)hGLP-1(7-36)NH₂ (SEQ ID NO:365)-   Example 323: (Aib^(8,35), Arg²⁶,    Glu³⁴(1-dodecylamino))hGLP-1(7-36)NH₂ (SEQ ID NO:366)-   Example 324: (Aib^(8,35,37) Arg^(26,24),    Glu³⁸(1-dodecylamino))hGLP-1(7-38)NH₂ (SEQ ID NO:367)-   Example 325: (Aib^(8,35), Arg³⁴,    Lys²⁶(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH₂ (SEQ    ID NO:368)-   Example 326: (Aib^(8,35), Arg³⁴,    Lys²⁶(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH₂    (SEQ ID NO:369)-   Example 327: (Aib^(8,35), Arg³⁴,    Lys²⁶(N^(ε)(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂    (SEQ ID NO:370-   Example 328: (Aib^(8,35), Arg³⁴,    Lys²⁶(N^(ε)(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH₂ (SEQ    ID NO:371)-   Example 329: (Aib^(8,35), Arg²⁶,    Lys³⁴(N^(ε)(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ (SEQ    ID NO:372)-   Example 330: (Aib^(8,35), Arg²⁶,    Lys³⁴(N^(ε)(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ (SEQ    ID NO:373)-   Example 331: (Aib^(8,35), Arg²⁶,    Lys³⁴(N^(ε)(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂    (SEQ ID NO:374)-   Example 332: (Aib^(8,35), Arg²⁶, Lys³⁴    (N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ (SEQ    ID NO:375)-   Example 333: (Aib^(8,35), Arg^(26,34),    Lys³⁶(N^(ε)-(2(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ (SEQ    ID NO:376)-   Example 334: (Aib^(8,35), Arg²⁶,34,    Lys³⁶(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂    (SEQ ID NO:377)-   Example 335: (Aib^(8,35), Arg^(26,34),    Lys³⁶(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂    (SEQ ID NO:378)-   Example 336: (Aib^(8,35), Arg^(26,34),    Lys³⁸(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-38)N H₂ (SEQ    ID NO:379)-   Example 337: (Aib^(8,35), Arg^(26,34),    Lys³(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ (SEQ    ID NO:380)-   Example 338: (Aib^(8,35), Arg^(26,34)    Lys³⁸(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂(SEQ    ID NO:381)-   Example 339: (Aib^(8,35), Arg^(26,34),    Lys³⁸(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂    (SEQ ID NO:382)-   Example 340: (Aib^(8,35,37), Arg^(26,34),    Lys³⁸(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7-38)NH₂ (SEQ    ID NO:383)-   Example 341: (Aib^(8,35,37), Arg^(26,34),    Lys³⁸(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂    (SEQ ID NO:384)-   Example 342: (Aib^(8,35,37), Arg^(26,34),    Lys³⁸(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-8)NH₂    (SEQ ID NO:385)-   Example 343: (Aib^(8,35,37), Arg^(26,34),    Lys³⁸(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-38)NH₂    (SEQ ID NO:386)-   Example 344: Aib^(8,35), Arg^(25,34), Lys²⁶    (N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH₂ (SEQ ID    NO:387)-   Example 344: (Aib^(8,35), Arg^(25,34),    Lys²⁶(N^(ε)(2-_4-dodecyl-1-piperazine)-acetyl)))hGLP)-1(7-36)NH₂(SEQ    ID NO:387)-   Example 345: (Aib^(8,35), Arg^(25,34),    Lys²⁶(N^(ε)(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ (SEQ    ID NO:388)-   Example 346: (Aib^(8,35), Arg^(25,34),    Lys²⁶(N^(ε)(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂    (SEQ ID NO:389)-   Example 347: (Aib^(8,35), Arg^(25,34),    Lys²⁶(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH₂    (SEQ ID NO:390)-   Example 348: (Aib^(8,35), Arg^(25,26), Lys³⁴    (N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ (SEQ ID    NO:391)-   Example 349: (Aib^(8,35), Arg^(25,26), Lys³⁴    (N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ (SEQ ID    NO:392)-   Example 350: (Aib^(8,35), Arg^(25,26),    Lys³⁴(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH₂    (SEQ ID NO:393)-   Example 351: (Aib^(8,35), Arg^(25,26),    Lys³⁴(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂    (SEQ ID NO:394)-   Example 352: (Aib^(8,35), Arg^(25,26,34)    Lys³⁶(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂ (SEQ    ID NO:395)-   Example 353: (Aib^(8,35), Arg^(25,26,34)    Lys³⁶(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH₂    (SEQ ID NO:396)-   Example 354: (Aib^(8,35), Arg^(25,26,34)    Lys³⁶(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂    (SEQ ID NO:397)-   Example 355: (Aib^(8,35), Arg^(25,26,34)    Lys³⁶(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH₂    (SEQ ID NO:398)-   Example 356: (Aib^(8,35), Arg^(25,26,34)    Lys³⁸(N^(ε)-(2(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ (SEQ    ID NO:399)-   Example 357: (Aib^(8,35), Arg^(25,26,34),    Lys³⁸(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂    (SEQ ID NO:400)-   Example 358: (Aib^(8,35), Arg^(25,26,34),    Lys³⁸(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))GLP-1(7-38)NH₂    (SEQ ID NO:401)-   Example 359: (Aib^(8,35), Arg^(25,26,34),    Lys³⁸(N^(ε)(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂    (SEQ ID NO:402)-   Example 360: (Aib^(8,35,37), Arg^(25,26,34),    Lys³⁸(N^(ε)-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂ (SEQ    ID NO:403)-   Example 361: (Aib^(8,35,37), Arg^(25,26,34),    Lys³⁸(N^(ε)-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂    (SEQ ID NO:404)-   Example 362: (Aib^(8,35,37), Arg^(25,26,34),    Lys³⁸(N^(ε)-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂    (SEQ ID NO:405)-   Example 363: (Aib^(8,35,37), Arg^(25,26,34),    Lys³⁸(N^(ε)-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH₂    (SEQ ID NO:406)-   Example 364: (Aib^(8,35), Arg^(26,34),    Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)OH (SEQ ID NO:407)-   Example 365: (Aib^(8,35), Lys²⁵, Arg^(26,34),    Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)OH (SEQ ID NO:408)-   Example 370: (Aib^(8,33), Arg^(26,34), Ava³⁷, Ado³⁹)hGLP-1(7-38)NH₂    (SEQ ID NO:409)-   Example 371: (Aib^(8,35), Arg^(26,34) Asp³⁷ Ava³⁸    Ado³⁹)hGLP-1(7-39)NH₂ (SEQ ID NO:27)-   Example 372: (Aib^(8,35), Arg^(26,34), Aun³⁷)hGLP-1(7-37)NH₂ (SEQ ID    NO:28)-   Example 373: (Aib^(8,17,35))hGLP-1(7-36)NH₂ (SEQ ID NO:29)-   Example 374: (Aib⁸, Arg^(26,34), β-Ala³⁵, D-Asp³⁷ Ava³⁸,    Aun³⁹)hGLP-1(7-39)NH₂ (SEQ ID NO:30)-   Example 375: (Gly⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:31)-   Example 376: (Ser⁸ , β-Ala ³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:32)-   Example 377: (Aib⁸, Glu^(22,23) Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:33)-   Example 378: (Gly⁸, Aib³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:34)-   Example 379: (Aib⁸, Lys¹⁸, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO: 35)-   Example 380: (Aib⁸, Leu²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:36)-   Example 381: (Aib⁸, Lys³³, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:37)-   Example 382: (Aib⁸, Lys⁸, Leu²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:38)-   Example 383: (Aib⁸, D-Arg³⁶)hGLP-1 (7-36)NH₂ (SEQ ID NO:39)-   Example 384: (Aib⁸, β-Ala³⁵, D-Arg³⁷)hGLP-1(7-37)NH₂ (SEQ ID NO:40)-   Example 385: (Aib^(8,27), β-Ala³⁵)hGLP-1 (7-36)NH₂ (SEQ ID NO:41)-   Example 386: (Aib^(8,27), β-Ala^(35,37) Arg³⁸)hGLP-(7-38)NH₂ (SEQ ID    NO:42)-   Example 387: (Aib^(8,27), β-Ala^(35,37)    Arg^(38,39))hGLP-1(7-39)NH₂(SEQ ID NO:43)-   Example 388: (Aib⁸, Lys^(18,27), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:44)-   Example 389: (Aib⁸, Lys²⁷, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:45)-   Example 390: (Aib⁸ , β-Ala ³⁵, Arg³⁸)hGLP-1(7-38)NH₂ (SEQ ID NO:46)-   Example 391: (Aib⁸, Arg^(26,34), β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:47)-   Example 392: (Aib⁸, D-Arg³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:48)-   Example 393: (Aib⁸, β-Ala³⁵, Arg³⁷)hGLP-1(7-37)NH₂ (SEQ ID NO:49)-   Example 394: (Aib⁸, Phe³¹ , β-Ala ³⁵)hGLP-1(7-36)NH₂ (SEQ ID NO:50)-   Example 395: (Aib^(8,35), Phe³¹, β-Ala³⁵)hGLP-1(7-36)NH₂ (SEQ ID    NO:51)-   Example 396: (Aib^(8,35), Nal³¹)hGLP-1(7-36)NH₂ (SEQ ID NO:52)-   Example 397: (Aib^(8,35), Nal^(28,31))hGLP-1(7-36)NH₂ (SEQ ID NO:53)-   Example 398: (Aib^(8,35) Arg^(26,34), Nal³¹)hGLP-1(7-36)NH₂ (SEQ ID    NO:54)-   Example 399: (Aib^(8,35), Arg^(26,34) Phe³¹)hGLP-1(7-36)NH₂ (SEQ ID    NO:55)-   Example 400: (Aib^(8,35), Nal^(19,31))hGLP-1(7-36)NH₂ (SEQ ID NO:56)-   Example 401: (Aib^(8,35), Nal^(12,31))hGLP-1 (7-36)NH₂ (SEQ ID    NO:57)-   Example 402: (Aib^(8,35), Lys³⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ    ID NO:58)-   Example 403: (Aib^(8,35), Arg³⁴,    Lys²⁶(N^(ε)-decanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:59)-   Example 404: (Aib^(8,35), Arg^(26,34),    Lys³⁶(N^(ε)-dodecanoyl))hGLP-1(7-36)NH₂ (SEQ ID NO:60)-   Example 405: (Aib⁸, β-Ala³⁵, Ser³⁷(O-decanoyl))hGLP-1(7-37)NH₂ (SEQ    ID NO:61)-   Example 406: (Aib^(8,27), β-Ala^(35,37), Arg³⁸,    Lys³⁷(N-octanoyl))hGLP-1(7-39)NH₂ (SEQ ID NO:62)-   Example 407: (Aib⁸, Arg^(26,34), β-Ala³⁵,    Lys³⁷(N^(ε)-octanoyl))hGLP-1(7-37)NH₂ (SEQ ID NO:63)-   Example 408: (Aib⁸, Arg^(26,34), β-Ala³⁵,    Lys³⁷(N^(ε)-decanoyl))hGLP-1(7-37)NH₂ (SEQ ID NO:64)-   Example 409: (Aib⁸, Arg^(26,34), β-Ala³⁵,    Lys³⁷(N^(ε)-6-tetradecanoyl))hGLP-1(7-37)NH₂ (SEQ ID NO:65)-   Example 410: (Aib⁸, Arg^(26,34), β-Ala³⁵,    Lys³⁷(N^(ε)-dodecanoyl))hGLP-1(7-37)NH₂ (SEQ ID NO:410)-   Example 411: (Aib⁸, Arg^(26,34), β-Ala³⁵,    Lys³⁷(N^(ε)-dodecanoyl))hGLP-1(8-37)NH₂ (SEQ ID NO:411)

Physical data for a representative sampling of the compounds exemplifiedherein are given in Table 1.

TABLE 1 Example Mol. Wt. Mol. Wt. Purity Number Expected MS(ES) (HPLC) 24 3351.8 3352.2 88%  26 3340.17 3340.9 99%  27 3353.81 3353.9 99%  293353.81 3353.9 99%  45 3352.6 3352.5 97%  51 3326.74 3326.6 99%  783395.81 3395.5 96% 136 3494 3494 99% 364 3523.02 3523.6 99% 365 3580.133580.3 95% 369 3677.25 3677 97% 370 3692.28 3692.4 98% 371 3807.373807.3 98% 372 3579.11 3579.7 97.90% 373 3337.81 3338.5 94% 374 3779.33779.5 94% 375 3297.7 3297.5 99% 376 3327.7 3327.4 98% 377 3398.8 3398.797.50% 378 3311.6 3311 93% 379 3366.85 3366.5 97% 380 3309.8 3309.4 99%381 3354.8 3354.5 97.70% 382 3350.9 3350.3 97.20% 383 3311.73 3310.7 92%384 3481.95 3481.3 94.30% 385 3281.76 3281.6 98% 386 3509.02 3509.199.40% 387 3665.2 3665.1 99% 388 3365.91 3365 97% 389 3324.79 3324.2 95%390 3539 3539.2 93% 391 3381.74 3381.3 97% 392 3410.89 3409.8 99% 3933481.95 3481.1 90% 394 3286.76 3286.2 99.20% 395 3300.76 3299.4 93% 3963350.81 3349.4 99% 397 3400.87 3400.1 99% 398 3406.84 3406.4 99% 3993356.77 3356.6 99% 400 3384.87 3384.43 94% 401 3400.87 3401.3 99% 4023466.03 3466.9 97.40% 403 3522.05 3522.06 93% 404 3550.11 3550.2 98% 4053567.09 99% 406 3763.38 3763.2 95% 407 3636.15 3635.8 99% 408 3664.213663.3 99% 409 3720.32 3719.5 99% 410 3692.27 3691.7 99% 411 3555.133554.4 99%

1. A compound wherein said compound is [Aib^(8,35)]hGLP-1(7-36)NH₂ (SEQID NO:2), or a pharmaceutically acceptable salt thereof.
 2. Acomposition comprising a compound according to claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent.